Furazanobenzimidazoles

ABSTRACT

The invention relates to compounds of formula (I) wherein R represents aryl or heteroaryl, X is oxygen, a carbonyl group, an oxime derivative of a carbonyl group or an α,β-unsaturated carbonyl group, and the substituents R 1  to R 6  have the meanings given in the specification, for use as medicaments, to novel compounds of formula (I), to methods of synthesis of such compounds, to pharmaceutical compositions containing compounds of formula (I), to the use of a compounds of formula (I) for the preparation of a pharmaceutical composition for the treatment of neoplastic and autoimmune diseases, and to methods of treatment of neoplastic and autoimmune diseases using such compounds of formula (I) or of pharmaceutical compositions containing same.

The invention relates to novel substituted furazanobenzimidazoles,processes for the preparation thereof, pharmaceutical compositionscontaining same, the use thereof optionally in combination with one ormore other pharmaceutically active compounds for the therapy ofneoplastic diseases and autoimmune diseases, and a method for thetreatment of such a diseases.

BACKGROUND OF THE INVENTION

Cancer is one of the leading causes of death in humans. Although avariety of drugs against neoplastic diseases have been developed andtechniques are available such as surgery and radiation therapy, there isstill a need for alternative and improved methods of treatment ofneoplastic diseases.

Autoimmune diseases are associated with abnormal lymphoproliferation asa result of defects in the termination of lymphocyte activation andgrowth. Often, such diseases are associated with inflammation likerheumatoid arthritis, insulin dependent diabetes mellitus, multiplesclerosis, systemic lupus erythematosus and the like. The treatment ofsuch diseases is focused on anti-inflammatory and immunosuppressivedrugs which in numerous cases show severe side effects. Hence, there isa need for alternative drugs with a new mode of action showing less sideeffects.

Apoptosis is a term used to describe a series of cellular events whichoccur to bring about programmed cell death. There are various apoptoticpathways, some of which have been characterized, whereas others remainto be elucidated. If the balance between cell division and apoptosis isdisturbed, life-threatening diseases including cancer, autoimmunedisorders, neurodegenerative and cardiovascular diseases may occur.

In recent years it has become evident that programmed cell death(apoptosis) is as important to the health of a multicellular organism ascell division. By repeated cell division and differentiation throughoutdevelopment or tissue repair, surplus or even harmful cells aregenerated. In order to maintain tissue homeostasis these cells have tobe removed or killed. The delicate interplay between cell growth andapoptosis in an organism is mirrored in the complex molecular balancethat determines whether an individual cell undergoes division, arrestsin the cell cycle or commits to programmed cell death.

Dysregulation of cell proliferation, or lack of appropriate cell death,has wide ranging clinical implications. A number of diseases associatedwith such dysregulation involve hyperproliferation, inflammation, tissueremodeling and repair. Familiar indications in this category includecancers, restenosis, neointimal hyperplasia, angiogenesis,endometriosis, lymphoproliferative disorders, transplantation relatedpathologies (graft rejection), polyposis, loss of neural function in thecase of tissue remodeling and the like. Such cells may lose the normalregulatory control of cell division, and may also fail to undergoappropriate cell death.

As apoptosis is inhibited or delayed in most types of proliferative,neoplastic diseases, induction of apoptosis is an option for treatmentof cancer, especially in cancer types which show resistance to classicchemotherapy, radiation and immunotherapy (Apoptosis and CancerChemotherapy, Hickman and Dive, eds., Blackwell Publishing, 1999). Alsoin autoimmune and transplantation related diseases and pathologiescompounds inducing apoptosis may be used to restore normal cell deathprocesses and therefore can eradicate the symptoms and might cure thediseases. Further applications of compounds inducing apoptosis may be inrestenosis, i.e. accumulation of vascular smooth muscle cells in thewalls of arteries, and in persistent infections caused by a failure toeradicate bacteria- and virus-infected cells. Furthermore, apoptosis canbe induced or re-established in epithelial cells, in endothelial cells,in muscle cells, and in others which have lost contact withextracellular matrix. These cells are potentially able to colonize otherorgans and therefore can develop into pathologies like neoplasias,endometriosis and the like.

Recently, a patent application was published disclosing a number ofstructurally related compounds (WO 03/066629). These compounds aredescribed as being inhibitors of GSK-3 and LCK kinase, but have norelevance in apoptosis and medical conditions connected therewith.

SUMMARY OF THE INVENTION

Furazanobenzimidazoles of formula (I) are selectively inducing apoptosisin cancer cells, and can be used for the treatment of neoplastic andautoimmune diseases. The invention relates to compounds of formula (I),in particular to such compounds for use as medicaments, to methods ofsynthesis of such compounds, to pharmaceutical compositions containingcompounds of formula (I), to the use of a compounds of formula (I) forthe preparation of a pharmaceutical composition for the treatment ofneoplastic and autoimmune diseases, and to methods of treatment ofneoplastic and autoimmune diseases using such compounds of formula (I)or of pharmaceutical compositions containing same.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to compounds of formula (I)

whereinR represents aryl or heteroaryl optionally substituted by up to foursubstituents independently selected fromalkyl, cycloalkyl, cycloalkyl-lower alkyl, halo-lower alkyl,hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-loweralkoxy-lower alkyl, halo-lower alkoxy-lower alkyl, acyloxy-lower alkyl,heterocyclyl, heterocyclyl-lower alkyl, optionally substituted phenyl,optionally substituted phenyl-lower alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl-lower alkyl, optionallysubstituted alkenyl, optionally substituted alkinyl, hydroxy, loweralkoxy, optionally substituted alkenyloxy, optionally substitutedalkinyloxy, cycloalkoxy, halo-lower alkoxy, cycloalkyl-lower alkoxy,hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, heterocyclyloxy,heterocyclyl-lower alkoxy, optionally substituted phenyloxy, optionallysubstituted phenyl-lower alkoxy, optionally substituted heteroaryloxy,optionally substituted heteroaryl-lower alkoxy, sulfamoyloxy,carbamoyloxy, lower alkylcarbonyloxy,amino, monoalkylamino, dialkylamino, aminocarbonylamino wherein each ofthe two amino groups is optionally substituted by alkyl, alkenyl,alkinyl or alkoxy-lower alkyl, heterocyclylcarbonylamino whereinheterocyclyl is bound via a nitrogen atom, aminosulfonylamino whereineach of the two amino groups is optionally substituted by alkyl,alkenyl, alkinyl or alkoxy-lower alkyl, heterocyclylsulfonylaminowherein heterocyclyl is bound via a nitrogen atom, loweralkoxycarbonylamino, lower alkylcarbonylamino wherein alkyl isoptionally substituted by one or two substituents selected fromoptionally substituted phenyl, guanidyl, halogen, cyano, alkoxy,optionally substituted phenoxy, alkylmercapto and optionally substitutedamino; lower alkenylcarbonylamino wherein alkenyl is optionallysubstituted by one or two substituents selected from lower alkyl,halo-lower alkyl, optionally substituted phenyl, halogen, cyano, alkoxyand optionally substituted amino; amino-lower alkyl or amino-loweralkylamino, wherein the nitrogen atom is unsubstituted or substituted byone or two substitutents selected from lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,optionally substituted phenyl, optionally substituted phenyl-loweralkyl, optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the twosubstituents on nitrogen form together with the nitrogen heterocyclyl,lower alkylcarbonyl, formyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl,carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, loweralkoxy-lower alkoxycarbonyl, optionally substituted phenyl-loweralkoxycarbonyl, cyano, lower alkylmercapto, optionally substitutedphenylmercapto, lower alkylsulfinyl, halo-lower alkylsulfinyl,optionally substituted phenylsulfinyl, lower alkylsulfonyl, halo-loweralkylsulfonyl, optionally substituted phenylsulfonyl, aralkylsulfonyl,halogen, and nitro;and wherein two adjacent substituents together with the atoms of aryl orheteroaryl may form a 5 or 6 membered carbocyclic or heterocyclic ring;X represents oxygen; a group C═Y, wherein Y stands for oxygen ornitrogen substituted by hydroxy or alkoxy; or a group —CO—CH═CH— whereinthe C═C bond is connected to R;R¹ and R², independently of each other, represent hydrogen, alkyl,cycloalkyl, cycloalkyl-alkyl, optionally substituted arylalkyl,optionally substituted heteroarylalkyl, hydroxyalkyl, alkoxyalkyl,hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, cyanoalkyl, optionallysubstituted alkenyl, optionally substituted alkinyl, or loweralkylcarbonyl wherein lower alkyl is optionally substituted by one ortwo substitutents selected from aryl, optionally substituted amino,alkoxy and aryloxy,R³, R⁴, R⁵ and R⁶, independently of each other, represent hydrogen,lower alkyl, halo-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl,hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-loweralkoxy-lower alkyl, halo-lower alkoxy-lower alkyl, heterocyclyl,heterocyclyl-lower alkyl, optionally substituted phenyl, optionallysubstituted phenyl-lower alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl-lower alkyl, optionally substitutedalkenyl, optionally substituted alkinyl,hydroxy, lower alkoxy, halo-lower alkoxy, cycloalkoxy, cycloalkyl-loweralkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy,heterocyclyloxy, heterocyclyl-lower alkoxy, optionally substitutedphenyloxy, optionally substituted phenyl-lower alkoxy, optionallysubstituted heteroaryloxy, optionally substituted heteroaryl-loweralkoxy,amino, carbamoyl, sulfamoyl, amino-lower alkyl or amino-loweralkylamino, wherein in each case the nitrogen atom is unsubstituted orsubstituted by one or two substitutents selected from lower alkyl,cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, loweralkoxy-lower alkyl, optionally substituted phenyl, optionallysubstituted phenyl-lower alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl-lower alkyl and lower alkylcarbonyl,or wherein the two substituents on nitrogen form together with thenitrogen heterocyclyl,lower alkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl,carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, loweralkoxy-lower alkoxycarbonyl, optionally substituted phenyl-loweralkoxycarbonyl, cyano,lower alkylmercapto, optionally substituted phenylmercapto, loweralkylsulfinyl, halo-lower alkylsulfinyl, optionally substitutedphenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl,optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, ornitro,or R³ and R⁴, R⁴ and R⁵, or R⁵ and R⁶ together with the atoms of thephenyl ring form a 5 or 6 membered carbocyclic or heterocyclic ring;and salts thereof.

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated:

The prefix “lower” denotes a radical having up to and including amaximum of 7, especially up to and including a maximum of 4 carbonatoms, the radicals in question being either linear or branched withsingle or multiple branching.

Where the plural form is used for compounds, salts, and the like, thisis taken to mean also a single compound, salt, or the like.

Double bonds in principle can have E- or Z-configuration. The compoundsof this invention may therefore exist as isomeric mixtures or singleisomers. If not specified both isomeric forms are intended.

Any asymmetric carbon atoms may be present in the (R)-, (S)- or(R,S)-configuration, preferably in the (R)- or (S)-configuration. Thecompounds may thus be present as mixtures of isomers or as pure isomers,preferably as enantiomer-pure diastereomers.

The invention relates also to possible tautomers of the compounds offormula (I).

Alkyl has from 1 to 12, preferably from 1 to 7 carbon atoms, and islinear or branched. Alkyl is preferably lower alkyl.

Lower alkyl has 1 to 4 carbon atoms and is butyl, such as n-butyl,sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl,ethyl or methyl. Preferably lower alkyl is methyl or ethyl.

Cycloalkyl has preferably 3 to 7 ring carbon atoms, and may beunsubstituted or substituted, e.g. by lower alkyl or lower alkoxy.Cycloalkyl is, for example, cyclohexyl, cyclopentyl, ormethylcyclopentyl.

Aryl stands for a mono- or bicyclic fused ring aromatic group with 5 to10 carbon atoms, such as phenyl, 1-naphthyl or 2-naphthyl, or also apartially saturated bicyclic fused ring comprising a phenyl group, suchas indanyl, dihydro- or tetrahydronaphthyl.

In optionally substituted phenyl, substituents are preferably loweralkyl, lower alkoxy, lower alkoxy-lower alkoxy, methylenedioxy,halo-lower alkyl, lower alkoxy-lower alkyl, halo, or nitro.

Heteroaryl represents an aromatic group containing at least oneheteroatom selected from nitrogen, oxygen and sulfur, and is mono- orbicyclic. Monocyclic heteroaryl includes 5 or 6 membered heteroarylgroups containing 1, 2, 3 or 4 heteroatoms selected from nitrogen,sulfur and oxygen. Bicyclic heteroaryl includes 9 or 10 memberedfused-ring heteroaryl groups. Examples of heteroaryl include pyrrolyl,thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, benzo fused derivatives of suchmonocyclic heteroaryl groups, such as indolyl, benzimidazolyl orbenzofuryl, quinolinyl, isoquinolinyl, quinazolinyl, or purinyl.

In optionally substituted heteroaryl, substituents are preferably loweralkyl, lower alkoxy, lower alkoxy-lower alkoxy, amino, optionallysubstituted by one or two substituents selected from lower alkyl, loweralkenyl and alkylcarbonyl, halo-lower alkyl, lower alkoxy-lower alkyl,halo, or nitro.

Alkenyl contains one or more, e.g. two or three, double bonds, and ispreferably lower alkenyl, such as 1- or 2-butenyl, 1-propenyl, allyl orvinyl.

Alkinyl is preferably lower alkinyl, such as propargyl or acetylenyl.

In optionally substituted alkenyl or alkinyl, substituents arepreferably lower alkyl, lower alkoxy, halo or di(lower alkyl)amino, andare connected with a saturated carbon atom of alkenyl or alkinyl or withan unsaturated carbon atom of alkenyl.

Heterocyclyl designates preferably a saturated, partially saturated orunsaturated, mono- or bicyclic ring containing 4-10 atoms comprisingone, two or three heteroatoms selected from nitrogen, oxygen and sulfur,which may, unless otherwise specified, be carbon or nitrogen linked,wherein a ring nitrogen atom may optionally be substituted by a groupselected from lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl andacyl, and a ring carbon atom may be substituted by lower alkyl,amino-lower alkyl, aryl, aryl-lower alkyl, heteroaryl, lower alkoxy,hydroxy or oxo. Examples of heterocyclyl are pyrrolidinyl, oxazolidinyl,thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxolanyl andtetrahydropyranyl.

Acyl designates, for example, alkylcarbonyl, cyclohexylcarbonyl,arylcarbonyl, aryl-lower alkylcarbonyl, or heteroarylcarbonyl. Loweracyl is preferably lower alkylcarbonyl, in particular propionyl oracetyl.

Hydroxyalkyl is especially hydroxy-lower alkyl, preferablyhydroxymethyl, 2-hydroxyethyl or 2-hydroxy-2-propyl.

Cyanoalkyl designates preferably cyanomethyl and cyanoethyl.

Haloalkyl is preferably fluoroalkyl, especially trifluoromethyl,3,3,3-trifluoroethyl or pentafluoroethyl.

Halogen is fluorine, chlorine, bromine, or iodine.

Lower alkoxy is especially methoxy, ethoxy, isopropyloxy, ortert-butyloxy.

Arylalkyl includes aryl and alkyl as defined hereinbefore, and is e.g.benzyl, 1-phenethyl or 2-phenethyl.

Heteroarylalkyl includes heteroaryl and alkyl as defined hereinbefore,and is e.g. 2-, 3- or 4-pyridylmethyl, 1- or 2-pyrrolylmethyl,1-pyrazolylmethyl, 1-imidazolylmethyl, 2-(1-imidazolyl)ethyl or3-(1-imidazolyl)propyl.

Two adjacent substituents which together with the atoms of aryl orheteroaryl may form a 5 or 6 membered carbocyclic or heterocyclic ringare, for example, propylene, 1- or 2-oxopropylene, 1- or 2-oxapropylene,1-oxapropylidene, methylenedioxy, difluoromethylenedioxy, 1- or2-azapropylene, 1- or 2-azapropylidene, 1,2- or 1,3-diazapropylidene,1,3-diaza-2-oxopropylene, butylene, 1- or 2-oxabutylene, ethylenedioxy,1- or 2-azabutylene, or 1- or 2-azabutadienylidene, or such groupscarrying further substituents as defined hereinbefore.

In substituted amino, the substituents are preferably those mentioned assubstituents R¹ and R². In particular, substituted amino is alkylamino,dialkylamino, optionally substituted arylalkylamino, or loweralkylcarbonylamino, and also lower alkoxycarbonylamino or optionallysubstituted aminocarbonylamino.

When X represents a group C═Y, wherein Y stands for nitrogen substitutedby hydroxy, this corresponds to an oxime function. Oximes and thecorresponding oxime alkyl ethers (nitrogen substituted by alkoxy) may bepresent in E or Z form, or as mixture of isomers.

When X represents a group —CO—CH═CH— wherein the C═C bond is connectedto R, R is connected to the terminal carbon atom of the C═C bond. TheC═C bond may be present in E or Z form, preferably in E form.

Salts are especially the pharmaceutically acceptable salts of compoundsof formula (I).

Such salts are formed, for example, as acid addition salts, preferablywith organic or inorganic acids, from compounds of formula (I) with abasic nitrogen atom, especially the pharmaceutically acceptable salts.Suitable inorganic acids are, for example, halogen acids, such ashydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organicacids are, for example, carboxylic, phosphonic, sulfonic or sulfamicacids, for example acetic acid, propionic acid, octanoic acid, decanoicacid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid,succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid,malic acid, tartaric acid, citric acid, amino acids, such as glutamicacid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleicacid, cyclohexanecarboxylic acid, adamantane-carboxylic acid, benzoicacid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylaceticacid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid,2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,1,5-naphthalene-disulfonic acid, 2-, 3- or 4-methylbenzenesulfonic acid,methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid,N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamicacid, or other organic protonic acids, such as ascorbic acid.

For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. For therapeutic use, only pharmaceutically acceptablesalts or free compounds are employed (where applicable in the form ofpharmaceutical preparations), and these are therefore preferred.

In view of the close relationship between the novel compounds in freeform and those in the form of their salts, including those salts thatcan be used as intermediates, for example in the purification oridentification of the novel compounds, any reference to the freecompounds hereinbefore and hereinafter is to be understood as referringalso to the corresponding salts, as appropriate and expedient.

The compound of the formula (I) may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the formula (I). Examples of pro-drugs include in vivohydrolysable esters and amides of a compound of the formula (I).Particular pro-drugs considered are ester and amides of naturallyoccurring amino acids and ester or amides of small peptides, inparticular small peptides consisting of up to five, preferably two orthree amino acids as well as esters and amides of pegylated hydroxyacids, preferably hydroxy acetic acid and lactic acid. Pro-drug estersare formed from the acid function of the amino acid or the C terminal ofthe peptide and suitable hydroxy group(s) in the compound of formula(I). Pro-drug amides are formed from the amino function of the aminoacid or the N terminal of the peptide and suitable carboxy group(s) inthe compound of formula (I), or from the acid function of the amino acidor the C terminal of the peptide and suitable amino group(s) in thecompound of formula (I).

The compounds of formula (I) have valuable pharmacological properties.The invention also relates to compounds of formula (I) as definedhereinbefore for use as medicaments.

The efficacy of the compounds of the invention in inducing apoptosis intumor cells can be demonstrated as follows:

Relative fluorescent activities of suitable tumor cell lines transfectedwith green fluorescent protein (GFP) are measured in the presence ofcompounds of the invention and of standard tumor drugs, using the methoddescribed in WO 99/35493. Suitable tumor cell lines are A20.2J, a BALB/cB cell lymphoma, PB-3c, an IL-3 dependent, non tumorigenic mastocyteline isolated from the bone marrow of a DBA/2 mouse, Jurkat, a humanacute T cell leukemia cell line, K562, a human chronic myelogenousleukemia cell line, HL60, a human acute promyelocytic leukemia cellline, Ramos and Raji, human B-cell lymphoma cell lines, H9 and Hut78,human T-cell lymphoma cell lines, HeLa and KB, human squamous cellcarcinoma cell lines, MCF7, SK-BR-3, PC3, HBL-100, SW480, H460 andH1792, human adenocarcinoma cell lines and HT-1080, a human fibrosarcomacell line.

Preferred standard drugs as compounds for comparisons are: a)antimetabolites such as 5-fluorouracil (ICN), gemcitabine HCl (Gemzar™,Eli Lilly), b) alkylating agents such as oxaliplatin (Eloxantin™,Sanofi-Synthélabo), dacarbazin (Detimedac™, Medac), cyclophosphamide(Endoxan™, Asta) and carboplatin (Paraplatin™, Bristol-Meyers Squibb),c) cell-cycle inhibitor such as vinorelbine (Navelbine™, Robapharm),vinblastine (Velbe™, Eli Lilly), docetaxel (Taxotere™, Aventis), d) DNAbreaker (topo-isomerase inhibitor, intercalator, strand breaker) such asdoxorubicin HCl (Adriblastin™, Pharmacia-Upjohn), bleomycin(Asta-Medica), irinotecan (Campto™, Aventis), etoposide phosphate(Etopophos™, Bristol-Meyers Squibb), topotecan HCl, (Hycamtin™,GlaxoSmithKline), e) mixtures thereof, f) compounds interfering with thesignal transduction pathway, such as caspase activity modifiers,agonists and antagonists of cell death receptors, modifiers ofnucleases, phosphatases and kinases such as imatinib mesylate (Gleevec™,Novartis), dexamethasone, phorbol myristate acetate, cyclosporin A,quercetin, tamoxifen (Alexis Corporation, Switzerland).

Apoptosis is determined in a primary screen using a fluorescence platereader and then in a secondary screen using FACS (fluorescence activatedcell scanning). Compounds causing apoptosis without substantialcytotoxic side effects are chosen for further testing andcharacterization by using a combination of the following wellestablished assays: A) Nuclear staining with Hoechst 33342 dye providinginformation about nuclear morphology and DNA fragmentation which arehallmarks of apoptosis. B) MTS proliferation assay measuring themetabolic activity of cells. Viable cells are metabolically activewhereas cells with compromised respiratory chain show a reduced activityin this test. C) AnnexinV binding assay which reflects thephosphatidylserine content of the outer lipid bilayer of the plasmamembrane. This event is considered an early hallmark of apoptosis. D) PIstaining for cell cycle distribution which shows any alterations in thedistribution among the different phases of the cell cycle. Cell cyclearresting points can be determined. E) Proliferation assay monitoringDNA synthesis by incorporating bromodeoxyuridine (BrdU). Inhibitoryeffects on growth/proliferation can be directly determined. F) Cysteinproteinase dependency, respectively caspase dependency are determined byusing specific inhibitors. This provides information about possibleinvolvement of specific proteases in the mechanisms.

On the basis of these studies, a compound of formula (I) according tothe invention shows therapeutic efficacy especially against neoplasticdiseases and autoimmune diseases. In particular, the compounds of theinvention are active against malignancies, e.g. epithelial neoplasms,squamous cell neoplasms, basal cell neoplasms, transitional cellpapillomas and carcinomas, adenomas und adenocarcinomas, adnexal andskin appendage neoplasms, mucoepidermoid neoplasms, cystic neoplasms,mucinous and serous neoplasms, ductal-, lobular and medullary neoplasms,acinar cell neoplasms, complex epithelial neoplasms, specialized gonadalneoplasms, paragangliomas and glomus tumors, naevi and melanomas, softtissue tumors and sarcomas, fibromatous neoplasms, myxomatous neoplasms,lipomatous neoplasms, myomatous neoplasms, complex mixed and stromalneoplasms, fibroepithelial neoplasms, synovial like neoplasms,mesothelial neoplasms, germ cell neoplasms, trophoblastic neoplasms,mesonephromas, blood vessel tumors, lymphatic vessel tumors, osseous andchondromatous neoplasms, giant cell tumors, miscellaneous bone tumors,odontogenic tumors, gliomas, neuroepitheliomatous neoplasms,meningiomas, nerve sheath tumors, granular cell tumors and alveolar softpart sarcomas, Hodgkin's and non Hodgkin's lymphomas, otherlymphoreticular neoplasms, plasma cell tumors, mast cell tumors,immunoproliferative diseases, leukemias, miscellaneousmyeloproliferative disorders, lymphoproliferative disorders andmyelodysplastic syndromes.

In particular, a compound of formula (I) according to the inventionshows therapeutic efficacy especially against solid neoplastic diseases,e.g. epithelial neoplasms, squamous cell neoplasms, basal cellneoplasms, transitional cell papillomas and carcinomas, adenomas undadenocarcinomas, adnexal and skin appendage neoplasms, mucoepidermoidneoplasms, cystic neoplasms, mucinous and serous neoplasms, ductal-,lobular and medullary neoplasms, acinar cell neoplasms, complexepithelial neoplasms, specialized gonadal neoplasms, paragangliomas andglomus tumors, naevi and melanomas, soft tissue tumors and sarcomas,fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms,myomatous neoplasms, complex mixed and stromal neoplasms,fibroepithelial neoplasms, synovial like neoplasms, mesothelialneoplasms, germ cell neoplasms, trophoblastic neoplasms, mesonephromas,blood vessel tumors, lymphatic vessel tumors, osseous and chondromatousneoplasms, giant cell tumors, miscellaneous bone tumors, odontogenictumors, gliomas, neuroepitheliomatous neoplasms, meningiomas, nervesheath tumors, granular cell tumors and alveolar soft part sarcomas.

The compounds of the invention are likewise active against autoimmunediseases, e.g. against systemic, discoid or subacute cutaneous lupuserythematosus, rheumatoid arthritis, antiphospholipid syndrome, CREST,progressive systemic sclerosis, mixed connective tissue disease (Sharpsyndrome), Reiter's syndrome, juvenile arthritis, cold agglutinindisease, essential mixed cryoglobulinemia, rheumatic fever, ankylosingspondylitis, chronic polyarthritis, myasthenia gravis, multiplesclerosis, chronic inflammatory demyelinating polyneuropathy,Guillan-Barré syndrome, dermatomyositis/polymyositis, autoimmunehemolytic anemia, thrompocytopenic purpura, neutropenia, type I diabetesmellitus, thyroiditis (including Hashimoto's and Grave' disease),Addison's disease, polyglandular syndrome, pemphigus (vulgaris,foliaceus, sebaceous and vegetans), bullous and cicatricial pemphigoid,pemphigoid gestationis, epidermolysis bullosa acquisita, linear IgAdisease, lichen sclerosus et atrophicus, morbus Duhring, psoriasisvulgaris, guttate, generalized pustular and localized pustularpsoriasis, vitiligo, alopecia greata, primary biliary cirrhosis,autoimmune hepatitis, all forms of glomerulo-nephritis, pulmonalhemorrhage (goodpasture syndrome), IgA nephropathy, pernicious anemiaand autoimmune gastritis, inflammatory bowel diseases (including colitisulcerosa and morbus Crohn), Behcet's disease, Celic-Sprue disease,autoimmune uveitis, autoimmune myocarditis, granulomatous orchitis,aspermatogenesis without orchitis, idiopatic and secondary pulmonaryfibrosis, inflammatory diesases with a possibility of autoimmunepathogensesis, such as pyoderma gangrensosum, lichen ruber, sarcoidosis(including Löfgren and cutaneous/subcutaneous type), granuloma anulare,allergic type I and type IV immunolgical reaction, asthma bronchiale,pollinosis, atopic, contact and airborne dermatitis, large vesselvasculitis (giant cell and Takayasu's arteritis), medium sized vesselvasculitis (polyarteritis nodosa, Kawasaki disease), small vesselvasculitis (Wegener's granulomatosis, Churg Strauss syndrome,microscopic polangiitis, Henoch-Schoenlein purpura, essentialcryoglobulinemic vasculitis, cutaneous leukoklastic angiitis),hypersensitivity syndromes, toxic epidermal necrolysis (Stevens-Johnsonsyndrome, erythema multiforme), diseases due to drug side effects, allforms of cutaneous, organ-specific and systemic effects due to type I-VI(Coombs classification) immunologic forms of reaction, transplantationrelated pathologies, such as acute and chronic graft versus host andhost versus graft disease, involving all organs (skin, heart, kidney,bone marrow, eye, liver, spleen, lung, muscle, central and peripheralnerve system, connective tissue, bone, blood and lymphatic vessel,genito-urinary system, ear, cartillage, primary and secondary lymphaticsystem including bone marrow, lymph node, thymus, gastrointestinaltract, including oro-pharynx, esophageus, stomach, small intestine,colon, and rectum, including parts of above mentioned organs down tosingle cell level and substructures, e.g. stem cells).

A compound of formula (I) can be administered alone or in combinationwith one or more other therapeutic agents, possible combination therapytaking the form of fixed combinations, or the administration of acompound of the invention and one or more other therapeutic agents beingstaggered or given independently of one another, or the combinedadministration of fixed combinations and one or more other therapeuticagents. A compound of formula (I) can, besides or in addition, beadministered especially for tumor therapy in combination withchemotherapy, radiotherapy, immunotherapy, surgical intervention, or acombination of these. Long-term therapy is equally possible as isadjuvant therapy in the context of other treatment strategies, asdescribed above. Other possible treatments are therapy to maintain thepatient's status after tumor regression, or even chemopreventivetherapy, for example in patients at risk. Particularly preferred is theuse of compounds of formula (I) in combination with radiotherapy.

Therapeutic agents for possible combination are especially one or morecytostatic or cytotoxic compounds, for example a chemotherapeutic agentor several selected from the group comprising indarubicin, cytarabine,interferon, hydroxyurea, bisulfan, or an inhibitor of polyaminebiosynthesis, an inhibitor of protein kinase, especially ofserine/threonine protein kinase, such as protein kinase C, or oftyrosine protein kinase, such as epidermal growth factor receptortyrosine kinase, a cytokine, a negative growth regulator, such as TGF-βor IFN-β, an aromatase inhibitor, a classical cytostatic, an inhibitorof the interaction of an SH2 domain with a phosphorylated protein, aninhibitor of Bcl-2 and modulators of the Bcl-2 family members such asBax, Bid, Bad, Bim, Nip3 and BH3-only proteins.

A compound according to the invention is not only for the (prophylacticand preferably therapeutic) management of humans, but also for thetreatment of other warm-blooded animals, for example of commerciallyuseful animals, for example rodents, such as mice, rabbits or rats, orguinea-pigs. Such a compound may also be used as a reference standard inthe test systems described above to permit a comparison with othercompounds.

With the groups of preferred compounds of formula (I) mentionedhereinafter, definitions of substituents from the general definitionsmentioned hereinbefore may reasonably be used, for example, to replacemore general definitions with more specific definitions or especiallywith definitions characterized as being preferred.

In particular, the invention relates to compounds of formula (I) wherein

R represents aryl or heteroaryl optionally substituted by up to foursubstituents independently selected from

alkyl, cycloalkyl, cycloalkyl-lower alkyl, halo-lower alkyl,hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-loweralkoxy-lower alkyl, halo-lower alkoxy-lower alkyl, acyloxy-lower alkyl,heterocyclyl, heterocyclyl-lower alkyl, optionally substituted phenyl,optionally substituted phenyl-lower alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl-lower alkyl, optionallysubstituted alkenyl, optionally substituted alkinyl, hydroxy, loweralkoxy, optionally substituted alkenyloxy, optionally substitutedalkinyloxy, cycloalkoxy, halo-lower alkoxy, cycloalkyl-lower alkoxy,hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, heterocyclyloxy,heterocyclyl-lower alkoxy, optionally substituted phenyloxy, optionallysubstituted phenyl-lower alkoxy, optionally substituted heteroaryloxy,optionally substituted heteroaryl-lower alkoxy, sulfamoyloxy,carbamoyloxy, lower alkylcarbonyloxy,

amino, monoalkylamino, dialkylamino, aminocarbonylamino wherein each ofthe two amino groups is optionally substituted by alkyl, alkenyl,alkinyl or alkoxy-lower alkyl, heterocyclylcarbonylamino whereinheterocyclyl is bound via a nitrogen atom, aminosulfonylamino whereineach of the two amino groups is optionally substituted by alkyl,alkenyl, alkinyl or alkoxy-lower alkyl, heterocyclylsulfonylaminowherein heterocyclyl is bound via a nitrogen atom, loweralkoxycarbonylamino, lower alkylcarbonylamino wherein alkyl isoptionally substituted by one or two substituents selected fromoptionally substituted phenyl, guanidyl, halogen, cyano, alkoxy,optionally substituted phenoxy, alkylmercapto and optionally substitutedamino; lower alkenylcarbonylamino wherein alkenyl is optionallysubstituted by one or two substituents selected from lower alkyl,halo-lower alkyl, optionally substituted phenyl, halogen, cyano, alkoxyand optionally substituted amino; amino-lower alkyl or amino-loweralkylamino, wherein the nitrogen atom is unsubstituted or substituted byone or two substitutents selected from lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,optionally substituted phenyl, optionally substituted phenyl-loweralkyl, optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the twosubstituents on nitrogen form together with the nitrogen heterocyclyl,lower alkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl,

carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, loweralkoxy-lower alkoxycarbonyl, optionally substituted phenyl-loweralkoxycarbonyl, cyano,

lower alkylmercapto, optionally substituted phenylmercapto, loweralkylsulfinyl, halo-lower alkylsulfinyl, optionally substitutedphenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl,optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, andnitro;

and wherein two adjacent substituents together with the atoms of aryl orheteroaryl may form a 5 or 6 membered carbocyclic or heterocyclic ring;

X represents oxygen; or a group C═Y, wherein Y stands for oxygen,nitrogen substituted by hydroxy or alkoxy;

R¹ and R², independently of each other, represent hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, optionally substituted arylalkyl,optionally substituted heteroarylalkyl, hydroxyalkyl, alkoxyalkyl,hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, cyanoalkyl, optionallysubstituted alkenyl, optionally substituted alkinyl, or loweralkylcarbonyl wherein lower alkyl is optionally substituted by one ortwo substitutents selected from aryl, optionally substituted amino,alkoxy and aryloxy,

R³, R⁴, R⁵ and R⁶, independently of each other, represent hydrogen,lower alkyl, halo-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl,hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-loweralkoxy-lower alkyl, halo-lower alkoxy-lower alkyl, heterocyclyl,heterocyclyl-lower alkyl, optionally substituted phenyl, optionallysubstituted phenyl-lower alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl-lower alkyl, optionally substitutedalkenyl, optionally substituted alkinyl,

hydroxy, lower alkoxy, halo-lower alkoxy, cycloalkoxy, cycloalkyl-loweralkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy,heterocyclyloxy, heterocyclyl-lower alkoxy, optionally substitutedphenyloxy, optionally substituted phenyl-lower alkoxy, optionallysubstituted heteroaryloxy, optionally substituted heteroaryl-loweralkoxy,

amino, carbamoyl, sulfamoyl, amino-lower alkyl or amino-loweralkylamino, wherein in each case the nitrogen atom is unsubstituted orsubstituted by one or two substitutents selected from lower alkyl,cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, loweralkoxy-lower alkyl, optionally substituted phenyl, optionallysubstituted phenyl-lower alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl-lower alkyl and lower alkylcarbonyl,or wherein the two substituents on nitrogen form together with thenitrogen heterocyclyl,

lower alkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl,

carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, loweralkoxy-lower alkoxycarbonyl, optionally substituted phenyl-loweralkoxycarbonyl, cyano,

lower alkylmercapto, optionally substituted phenylmercapto, loweralkylsulfinyl, halo-lower alkylsulfinyl, optionally substitutedphenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl,optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, ornitro,

or R³ and R⁴, R⁴ and R⁵, or R⁵ and R⁶ together with the atoms of thephenyl ring form a 5 or 6 membered carbocyclic or heterocyclic ring;

and salts thereof.

More particularly the invention relates to compounds of formula (I)wherein

R represents phenyl, naphthyl, thienyl, furyl, thiazolyl, oxadiazolyl,thiadiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl,benzothienyl, benzofuryl, indolyl, benzoisoxazolyl, optionallysubstituted by up to four substituents independently selected fromalkyl, cycloalkyl, cycloalkyl-lower alkyl, halo-lower alkyl,hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-loweralkoxy-lower alkyl, halo-lower alkoxy-lower alkyl, acyloxy-lower alkyl,heterocyclyl, heterocyclyl-lower alkyl, optionally substituted phenyl,optionally substituted phenyl-lower alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl-lower alkyl, optionallysubstituted alkenyl, optionally substituted alkinyl, hydroxy, loweralkoxy, optionally substituted alkenyloxy, optionally substitutedalkinyloxy, cycloalkoxy, halo-lower alkoxy, cycloalkyl-lower alkoxy,hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, heterocyclyloxy,heterocyclyl-lower alkoxy, optionally substituted phenyloxy, optionallysubstituted phenyl-lower alkoxy, optionally substituted heteroaryloxy,optionally substituted heteroaryl-lower alkoxy, sulfamoyloxy,carbamoyloxy, lower alkylcarbonyloxy,

amino, monoalkylamino, dialkylamino, aminocarbonylamino wherein each ofthe two amino groups is optionally substituted by alkyl, alkenyl,alkinyl or alkoxy-lower alkyl, heterocyclylcarbonylamino whereinheterocyclyl is bound via a nitrogen atom, aminosulfonylamino whereineach of the two amino groups is optionally substituted by alkyl,alkenyl, alkinyl or alkoxy-lower alkyl, heterocyclylsulfonylaminowherein heterocyclyl is bound via a nitrogen atom, loweralkoxycarbonylamino, lower alkylcarbonylamino wherein alkyl isoptionally substituted by one or two substituents selected fromoptionally substituted phenyl, guanidyl, halogen, cyano, alkoxy,optionally substituted phenoxy, alkylmercapto and optionally substitutedamino; lower alkenylcarbonylamino wherein alkenyl is optionallysubstituted by one or two substituents selected from lower alkyl,halo-lower alkyl, optionally substituted phenyl, halogen, cyano, alkoxyand optionally substituted amino; amino-lower alkyl or amino-loweralkylamino, wherein the nitrogen atom is unsubstituted or substituted byone or two substitutents selected from lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,optionally substituted phenyl, optionally substituted phenyl-loweralkyl, optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the twosubstituents on nitrogen form together with the nitrogen heterocyclyl,lower alkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl,

carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, loweralkoxy-lower alkoxycarbonyl, optionally substituted phenyl-loweralkoxycarbonyl, cyano,

lower alkylmercapto, optionally substituted phenylmercapto, loweralkylsulfinyl, halo-lower alkylsulfinyl, optionally substitutedphenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl,optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, andnitro;

and wherein two adjacent substituents together with the atoms of aryl orheteroaryl may form a 5 or 6 membered carbocyclic or heterocyclic ring;

X represents oxygen; or a group C═Y, wherein Y stands for oxygen ornitrogen substituted by hydroxy or alkoxy;

R¹ and R², independently of each other, represent hydrogen, loweralkylcarbonyl or optionally substituted phenylcarbonyl;

R³, R⁴, R⁵ and R⁶, independently of each other, represent hydrogen,lower alkyl, halo-lower alkyl, alkoxy, hydroxy-lower alkoxy, loweralkoxy-lower alkoxy, amino, carbamoyl, sulfamoyl, amino-lower alkyl oramino-lower alkylamino, wherein in each case the nitrogen atom isunsubstituted or substituted by one or two substitutents selected fromlower alkyl, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl,lower alkoxy-lower alkyl, optionally substituted phenyl, optionallysubstituted phenyl-lower alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl-lower alkyl and loweralkylaminocarbonyl, or wherein the two substituents on nitrogen formtogether with the nitrogen heterocyclyl, carboxy, lower alkoxycarbonyl,hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl,optionally substituted phenyl-lower alkoxycarbonyl, cyano,

lower alkylmercapto, optionally substituted phenylmercapto, loweralkylsulfinyl, halo-lower alkylsulfinyl, optionally substitutedphenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl,optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, ornitro,

or R³ and R⁴, R⁴ and R⁵, or R⁵ and R⁶ together represent methylenedioxy;

and salts thereof.

Preferred are compounds of formula (I) wherein

R represents phenyl, naphthyl, thienyl, furyl, thiazolyl, oxadiazolyl,thiadiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl,benzothienyl, benzofuryl, indolyl, benzoisoxazolyl, optionallysubstituted by up to four substituents independently selected fromalkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,lower alkoxy-lower alkoxy-lower alkyl, halo-lower alkoxy-lower alkyl,acyloxy-lower alkyl, heterocyclyl, heterocylyl-lower alkyl, optionallysubstituted phenyl, optionally substituted phenyl-lower alkyl,optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl, optionally substituted alkenyl, optionallysubstituted alkinyl,

hydroxy, lower alkoxy, optionally substituted alkenyloxy, optionallysubstituted alkinyloxy, cycloalkoxy, halo-lower alkoxy, cycloalkyl-loweralkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy,heterocyclyloxy, heterocyclyl-lower alkoxy, optionally substitutedphenyloxy, optionally substituted phenyl-lower alkoxy, optionallysubstituted heteroaryloxy, optionally substituted heteroaryl-loweralkoxy, sulfamoyloxy, carbamoyloxy, lower alkylcarbonyloxy,

amino, monoalkylamino, dialkylamino, aminocarbonylamino wherein each ofthe two amino groups is optionally substituted by alkyl, alkenyl,alkinyl or alkoxy-lower alkyl, heterocyclylcarbonylamino whereinheterocyclyl is bound via a nitrogen atom, aminosulfonylamino whereineach of the two amino groups is optionally substituted by alkyl,alkenyl, alkinyl or alkoxy-lower alkyl, heterocyclylsulfonylaminowherein heterocyclyl is bound via a nitrogen atom, loweralkoxycarbonylamino, lower alkylcarbonylamino wherein alkyl isoptionally substituted by one or two substituents selected fromoptionally substituted phenyl, guanidyl, halogen, cyano, alkoxy,optionally substituted phenoxy, alkylmercapto and optionally substitutedamino; lower alkenylcarbonylamino wherein alkenyl is optionallysubstituted by one or two substituents selected from lower alkyl,halo-lower alkyl, optionally substituted phenyl, halogen, cyano, alkoxyand optionally substituted amino; amino-lower alkyl or amino-loweralkylamino, wherein the nitrogen atom is unsubstituted or substituted byone or two substitutents selected from lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,optionally substituted phenyl, optionally substituted phenyl-loweralkyl, optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the twosubstituents on nitrogen form together with the nitrogen heterocyclyl,lower alkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl,

carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, loweralkoxy-lower alkoxycarbonyl, optionally substituted phenyl-loweralkoxycarbonyl, cyano,

lower alkylmercapto, optionally substituted phenylmercapto, loweralkylsulfinyl, halo-lower alkylsulfinyl, optionally substitutedphenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl,optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, andnitro;

and wherein two adjacent substituents together with the atoms of aryl orheteroaryl may form a 5 or 6 membered carbocyclic or heterocyclic ring;

X represents a group C═Y, wherein Y stands for oxygen or nitrogensubstituted by hydroxy or alkoxy;

R¹ and R², independently of each other, represent hydrogen or loweralkylcarbonyl;

R³, R⁴, R⁵ and R⁶, independently of each other, represent hydrogen,lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, carboxy, loweralkoxycarbonyl, cyano, halogen or nitro;

and salts thereof.

Most preferably, the invention relates to the compounds of the Examplesand pharmaceutically acceptable salts, especially to the compounds

-   4-(1-Phenacyl-1H-benzimidazol-2-yl)-furazan-3-ylamine;-   4-(1-Phenacyl-1H-benzimidazol-2-yl)-furazan-3-ylamine oxime;-   4-(1-Phenacyl-1H-benzimidazol-2-yl)-furazan-3-ylamine oxime methyl    ether;-   4-[1-(4-Bromophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;-   4-[1-(4-Bromophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine    oxime;-   4-[1-(4-Bromophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine oxime    methyl ether;-   4-[1-(4-Chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;-   4-[1-(4-Chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine    oxime;-   4-[1-(4-Chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine    oxime methyl ether;-   4-[1-(4-Methoxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;-   4-[1-(4-Methoxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine    oxime;-   4-[1-(3-Methoxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;-   4-[1-(3-Methoxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine    oxime;-   4-[1-(3-Methoxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine    oxime methyl ether;-   4-[1-(4-Phenylphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;-   4-[1-(4-Phenylphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine    oxime;-   4-[1-(4-Phenylphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine    oxime methyl ether;-   and    4-[1-(2,4-Dichlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;    and to pharmaceutically acceptable salts thereof.

In another embodiment, the invention relates to compounds of formula (I)wherein

R represents phenyl, naphthyl, thienyl, furyl, thiazolyl, oxadiazolyl,thiadiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl,benzothienyl, benzofuryl, indolyl, benzoisoxazolyl, optionallysubstituted by up to four substituents independently selected fromalkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,lower alkoxy-lower alkoxy-lower alkyl, halo-lower alkoxy-lower alkyl,acyloxy-lower alkyl, heterocyclyl, heterocyclyl-lower alkyl, optionallysubstituted phenyl, optionally substituted phenyl-lower alkyl,optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl, optionally substituted alkenyl, optionallysubstituted alkinyl,

hydroxy, lower alkoxy, optionally substituted alkenyloxy, optionallysubstituted alkinyloxy, cycloalkoxy, halo-lower alkoxy, cycloalkyl-loweralkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy,heterocyclyloxy, heterocyclyl-lower alkoxy, optionally substitutedphenyloxy, optionally substituted phenyl-lower alkoxy, optionallysubstituted heteroaryloxy, optionally substituted heteroaryl-loweralkoxy, sulfamoyloxy, carbamoyloxy, lower alkylcarbonyloxy,

amino, monoalkylamino, dialkylamino, aminocarbonylamino wherein each ofthe two amino groups is optionally substituted by alkyl, alkenyl,alkinyl or alkoxy-lower alkyl, heterocyclylcarbonylamino whereinheterocyclyl is bound via a nitrogen atom, aminosulfonylamino whereineach of the two amino groups is optionally substituted by alkyl,alkenyl, alkinyl or alkoxy-lower alkyl, heterocyclylsulfonylaminowherein heterocyclyl is bound via a nitrogen atom, loweralkoxycarbonylamino, lower alkylcarbonylamino wherein alkyl isoptionally substituted by one or two substituents selected fromoptionally substituted phenyl, guanidyl, halogen, cyano, alkoxy,optionally substituted phenoxy, alkylmercapto and optionally substitutedamino; lower alkenylcarbonylamino wherein alkenyl is optionallysubstituted by one or two substituents selected from lower alkyl,halo-lower alkyl, optionally substituted phenyl, halogen, cyano, alkoxyand optionally substituted amino; amino-lower alkyl or amino-loweralkylamino, wherein the nitrogen atom is unsubstituted or substituted byone or two substitutents selected from lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,optionally substituted phenyl, optionally substituted phenyl-loweralkyl, optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the twosubstituents on nitrogen form together with the nitrogen heterocyclyl,lower alkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl,

carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, loweralkoxy-lower alkoxycarbonyl, optionally substituted phenyl-loweralkoxycarbonyl, cyano,

lower alkylmercapto, optionally substituted phenylmercapto, loweralkylsulfinyl, halo-lower alkylsulfinyl, optionally substitutedphenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl,optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, andnitro;

and wherein two adjacent substituents together with the atoms of aryl orheteroaryl may form a 5 or 6 membered carbocyclic or heterocyclic ring;

X represents a group C═Y, wherein Y stands for oxygen or nitrogensubstituted by hydroxy or alkoxy;

R¹ represents cyanoalkyl;

R² represents hydrogen;

R³, R⁴, R⁵ and R⁶, independently of each other, represent hydrogen,lower alkyl, halo-lower alkyl, hydroxy, lower alkoxy, carboxy, loweralkoxycarbonyl, cyano, halogen or nitro;

and salts thereof.

Alternatively, the invention relates to compounds of formula (I) whereinR, X and R² to R⁶ are as defined in the preceding paragraphs and R¹represents hydroxyalkyl, and salts thereof.

In yet another embodiment, the invention relates to compounds of formula(I) wherein

R represents phenyl, thienyl, pyridinyl or pyridazinyl, optionallysubstituted by one or two substituents independently selected from

alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,acyloxy-lower alkyl, phenyl,

hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy,phenyl-lower alkoxy, lower alkylcarbonyloxy,

amino, monoalkylamino, dialkylamino, lower alkoxycarbonylamino, loweralkylcarbonylamino, substituted amino wherein the two substituents onnitrogen form together with the nitrogen heterocyclyl,

lower alkylcarbonyl, formyl,

carboxy, lower alkoxycarbonyl, cyano,

halogen, and nitro;

and wherein two adjacent substituents are methylenedioxy;

X represents oxygen; a group C═Y, wherein Y stands for oxygen ornitrogen substituted by hydroxy or alkoxy; or a group —CO—CH═CH— whereinthe C═C bond is connected to R;

R¹ represents hydrogen, lower alkylcarbonyl, hydroxy-lower alkyl orcyano-lower alkyl;

R², R³ and R⁶ represent hydrogen;

R⁴ and R⁵, independently of each other, represent hydrogen, lower alkylor lower alkoxy;

or R⁴ and R⁵ together represent methylenedioxy;

and salts thereof.

Preferred are compounds of formula (I) wherein

R represents phenyl, thienyl, pyridinyl or pyridazinyl,

wherein phenyl is optionally substituted by one or two substituentsindependently selected from alkyl, halo-lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy,lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy,phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino,dialkylamino, lower alkoxycarbonylamino, lower alkylcarbonylamino,substituted amino wherein the two substituents on nitrogen form togetherwith the nitrogen heterocyclyl, lower alkylcarbonyl, formyl, carboxy,lower alkoxycarbonyl, cyano, halogen, and nitro; and wherein twoadjacent substituents are methylenedioxy;

and wherein pyridinyl or pyridazinyl are optionally substituted by loweralkoxy, amino or halogen;

X represents a group C═Y, wherein Y stands for oxygen or nitrogensubstituted by hydroxy or lower alkoxy;

R¹ represents hydrogen, lower alkylcarbonyl, hydroxy-lower alkyl orcyano-lower alkyl;

R², R³ and R⁶ represent hydrogen;

R⁴ and R⁵, independently of each other, represent hydrogen, lower alkylor lower alkoxy;

or R⁴ and R⁵ together represent methylenedioxy;

and pharmaceutically acceptable salts thereof.

More preferred are compounds of formula (I) wherein

R represents phenyl, thienyl or pyridinyl

wherein phenyl is optionally substituted by one or two substituentsindependently selected from alkyl, halo-lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy,lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy,phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino,dialkylamino, lower alkoxycarbonylamino, lower alkylcarbonylamino,substituted amino wherein the two substituents on nitrogen form togetherwith the nitrogen heterocyclyl, lower alkylcarbonyl, carboxy, loweralkoxycarbonyl, cyano, halogen, and nitro; and wherein two adjacentsubstituents are methylenedioxy;

and wherein pyridinyl is optionally substituted by lower alkoxy, aminoor halogen;

X represents a group C═Y, wherein Y stands for oxygen or nitrogensubstituted by hydroxy or lower alkoxy;

R¹ represents hydrogen, lower alkylcarbonyl, hydroxy-lower alkyl orcyano-lower alkyl;

R², R³ and R⁶ represent hydrogen;

R⁴ and R⁵, independently of each other, represent hydrogen, lower alkylor lower alkoxy;

or R⁴ and R⁵ together represent methylenedioxy;

and pharmaceutically acceptable salts thereof.

Particularly preferred are compounds of formula (I) wherein

R represents phenyl, thienyl, pyridinyl or pyridazinyl,

wherein phenyl is optionally substituted by one or two substituentsindependently selected from alkyl, halo-lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy,lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy,phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino,dialkylamino, lower alkoxycarbonylamino, lower alkylcarbonylamino,substituted amino wherein the two substituents on nitrogen form togetherwith the nitrogen heterocyclyl, lower alkylcarbonyl, formyl, carboxy,lower alkoxycarbonyl, cyano, halogen, and nitro; and wherein twoadjacent substituents are methylenedioxy;

and wherein pyridinyl or pyridazinyl are optionally substituted by loweralkoxy, amino or halogen;

X represents a group C═Y, wherein Y stands for oxygen or nitrogensubstituted by hydroxy or lower alkoxy;

R¹ represents cyano-lower alkyl;

R², R³ and R⁶ represent hydrogen;

R⁴ and R⁵, independently of each other, represent hydrogen, lower alkylor lower alkoxy;

or R⁴ and R⁵ together represent methylenedioxy;

and pharmaceutically acceptable salts thereof.

Highly preferred are compounds of formula (I) wherein

R represents phenyl or pyridinyl

wherein phenyl is optionally substituted by one or two substituentsindependently selected from alkyl, halo-lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy,lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy,phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino,dialkylamino, lower alkoxycarbonylamino, lower alkylcarbonylamino,substituted amino wherein the two substituents on nitrogen form togetherwith the nitrogen heterocyclyl, lower alkylcarbonyl, carboxy, loweralkoxycarbonyl, formyl, cyano, halogen, and nitro; and wherein twoadjacent substituents are methylenedioxy;

and wherein pyridinyl is optionally substituted by lower alkoxy, aminoor halogen;

X represents oxygen;

R¹ represents hydrogen, lower alkylcarbonyl, hydroxy-lower alkyl orcyano-lower alkyl;

R², R³ and R⁶ represent hydrogen;

R⁴ and R⁵, independently of each other, represent hydrogen, lower alkylor lower alkoxy;

or R⁴ and R⁵ together represent methylenedioxy;

and pharmaceutically acceptable salts thereof.

Likewise preferred are compounds of formula (I) wherein R and R¹ to R⁶are defined as in the preceding paragraphs, and X represents nitrogensubstituted by alkoxy, and pharmaceutically acceptable salts thereof.

Other preferred compounds that come into consideration are compounds offormula (I)

wherein

R represents phenyl or pyridinyl

wherein phenyl is optionally substituted by one or two substituentsindependently selected from alkyl, halo-lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy,lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy,phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino,dialkylamino, lower alkoxycarbonylamino, lower alkylcarbonylamino,substituted amino wherein the two substituents on nitrogen form togetherwith the nitrogen heterocyclyl, lower alkylcarbonyl, carboxy, loweralkoxycarbonyl, formyl, cyano, halogen, and nitro; and wherein twoadjacent substituents are methylenedioxy;

and wherein pyridinyl is optionally substituted by lower alkoxy, aminoor halogen;

X represents oxygen;

R¹ represents cyano-lower alkyl;

R², R³, R⁴, R⁵ and R⁶ represent hydrogen;

and pharmaceutically acceptable salts thereof.

More preferred are compounds of formula (I) wherein

R represents phenyl or pyridinyl

wherein phenyl is optionally substituted by one or two substituentsindependently selected from alkyl, lower alkoxy-lower alkyl,acyloxy-lower alkyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, loweralkoxy-lower alkoxy, amino, monoalkylamino, dialkylamino, loweralkoxycarbonylamino, lower alkylcarbonylamino, substituted amino whereinthe two substituents on nitrogen form together with the nitrogenheterocyclyl, halogen, and nitro;

and wherein two adjacent substituents are methylenedioxy;

and wherein pyridinyl is optionally substituted by lower alkoxy, aminoor halogen;

X represents oxygen;

R¹ represents cyano-lower alkyl;

R², R³, R⁴ ₉ R⁵ and R⁶ represent hydrogen;

and pharmaceutically acceptable salts thereof.

Particularly preferred are compounds of formula (I) according to claim 8wherein

R represents phenyl or pyridinyl

wherein phenyl is optionally substituted by one or two substituentsindependently selected from alkyl, lower alkoxy-lower alkyl,acyloxy-lower alkyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, loweralkoxy-lower alkoxy, amino, monoalkylamino, dialkylamino, loweralkoxycarbonylamino, lower alkylcarbonylamino, substituted amino whereinthe two substituents on nitrogen form together with the nitrogenheterocyclyl, halogen, and nitro;

and wherein two adjacent substituents are methylenedioxy;

and wherein pyridinyl is optionally substituted by lower alkoxy, aminoor halogen;

X represents nitrogen substituted by alkoxy;

R¹ represents cyano-lower alkyl;

R², R³, R⁴, R⁵ and R⁶ represent hydrogen;

and pharmaceutically acceptable salts thereof.

Other preferred compounds of formula (I) are those wherein

R represents phenyl optionally substituted by one or two substituentsindependently selected from alkyl, halo-lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy,lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy,phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino,dialkylamino, lower alkoxycarbonylamino, lower alkylcarbonylamino,substituted amino wherein the two substituents on nitrogen form togetherwith the nitrogen heterocyclyl, lower alkylcarbonyl, carboxy, loweralkoxycarbonyl, cyano, halogen, and nitro; and wherein two adjacentsubstituents are methylenedioxy;

X represents a group —CO—CH═CH— wherein the C═C bond is connected to R;

R¹ represents cyano-lower alkyl;

R², R³, R⁴, R⁵ and R⁶ represent hydrogen;

and pharmaceutically acceptable salts thereof.

Most preferred are compounds selected from the group consisting of

-   4-[1-(4-Chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine;-   4-[1-(3-Methoxy-4-methoxymethoxy-phenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;-   4-[1-(4-Bromophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine;-   4-[1-(4-Aminophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine;-   4-[1-(4-Methoxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine;-   4-[1-(3,4-Dimethylphenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine;-   4-[1-(4-Ethylphenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine;-   4-[1-(6-Chloro-3-pyridyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;-   4-[1-(6-Amino-3-pyridyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine;    and-   4-[1-(6-Amino-3-pyridyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;    and pharmaceutically acceptable salts thereof.

Especially, the invention relates to compounds as described hereinbeforefor use as medicaments.

The invention also relates to the use of a compound of formula (I), aprodrug or a pharmaceutically acceptable salt of such a compound for thepreparation of a pharmaceutical composition for the treatment of aneoplastic disease, autoimmune disease, transplantation relatedpathology and/or degenerative disease, in particular for the treatmentof a solid neoplastic disease.

Furthermore, the invention provides a method for the treatment of aneoplastic disease, autoimmune disease, transplantation relatedpathology and/or degenerative disease, in particular of a solidneoplastic disease, which comprises administering a compound of formula(I), a prodrug or a pharmaceutically acceptable salt thereof, whereinthe radicals and symbols have the meanings as defined above, in aquantity effective against said disease, to a warm-blooded animalrequiring such treatment.

Method of Preparation

A compound of the invention may be prepared by processes that, thoughnot applied hitherto for the new compounds of the present invention, areknown per se, in particularA) a process, wherein a compound of formula (II)

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are defined as for formula (I), or aderivative thereof with functional groups in protected form and/or asalt thereof, is alkylated with an alkylating agent of formula (III)R—X—CH₂-Z  (III)wherein R is as defined for formula (I), X is CO or —CO—CH═CH— and Z isa nucleophilic leaving group;orB) a process, wherein a compound of formula (II) wherein R¹, R². R³, R⁴,R⁵ and R⁶ are defined as for formula (I), or a derivative thereof withfunctional groups in protected form and/or a salt thereof, is alkylatedwith a mixture of a dihalomethane type compound of formula Z¹-CH₂-Z²(IV), wherein Z¹ and Z² are leaving groups, and a compound of formulaR—XH (V), wherein R is as defined for formula (I) and X is oxygen;any protecting groups in a protected derivative of a compound of theformula (I) are removed;and, if so desired, an obtainable compound of formula (I) is convertedinto another compound of formula (I), a free compound of formula (I) isconverted into a salt, an obtainable salt of a compound of formula (I)is converted into the free compound or another salt, and/or a mixture ofisomeric compounds of formula (I) is separated into the individualisomers.

Suitable nucleophilic leaving groups Z in an alkylating agent of formula(III) are for example halides, e.g. chloride, bromide or iodide, orsulfonates, e.g. aromatic sulfonic acid esters such asbenzenesulfonates, p-toluenesulfonates or p-nitrobenzenesulfonates, oralso methanesulfonate or trifluormethanesulfonate. Also other customaryleaving groups are considered, e.g. ammonium salts, azides, diazoniumsalts, di(p-toluenesulfonyl)-amines, nitrates, oxonium salts, sulfoniumsalts, or phosphonium salts. Suitable nucleophilic leaving groups Z¹ andZ² in a dihalomethane type compound formula (IV) are those mentionedabove, in particular chlorine, bromine and iodine.

Alkylation of a compound of formula (II) with an alkylating agent offormula (III) is performed in a manner known per se, usually in thepresence of a suitable polar or dipolar aprotic solvent, with cooling orheating, for example in a temperature range from approximately −30° C.to approximately +150° C., especially approximately around 0° C. to roomtemperature. Optionally a suitable base is added, in particularly atertiary amine base such as triethylamine or diisopropylethylamine, oran inorganic basic salt, e.g. potassium or sodium carbonate.

Mixed alkylation of a compound of formula (II) and of a compound offormula (V) with a dihalomethane type compound of formula (IV) isperformed in the presence of a suitable polar or dipolar aproticsolvent, with cooling or heating, for example in a temperature rangefrom approximately −30° C. to approximately +150° C., especiallyapproximately around 0° C. to room temperature. Suitable bases used inthis reaction are for example potassium and sodium carbonate.

If one or more other functional groups, for example carboxy, hydroxy oramino, are or need to be protected in a compound of formula (II), (III)or (V), because they should not take part in the reaction, these aresuch protecting groups as are usually applied in the synthesis ofamides, in particular peptide compounds, cephalosporins, penicillins,nucleic acid derivatives and sugars.

The protecting-groups may already be present in precursors and shouldprotect the functional groups concerned against unwanted secondaryreactions, such as alkylations, acylations, etherifications,esterifications, oxidations, solvolysis, and similar reactions. It is acharacteristic of protecting groups that they lend themselves readily,i.e. without undesired secondary reactions, to removal, typically bysolvolysis, reduction, photolysis or also by enzyme activity, forexample under conditions analogous to physiological conditions, and thatthey are not present in the end products. The specialist knows, or caneasily establish, which protecting groups are suitable with thereactions mentioned hereinabove and hereinafter.

The protection of such functional groups by such protecting groups, theprotecting groups themselves, and their removal reactions are describedfor example in standard reference books for peptide synthesis and inspecial books on protective groups such as J. F. W. McOmie, “ProtectiveGroups in Organic Chemistry”, Plenum Press, London and New York 1973, in“Methoden der organischen Chemie” (Methods of organic chemistry),Houben-Weyl, 4th edition, Volume 15/l, Georg Thieme Verlag, Stuttgart1974, and in T. W. Greene, “Protective Groups in Organic Synthesis”,Wiley, New York.

In the additional process steps, carried out as desired, functionalgroups of the starting compounds which should not take part in thereaction may be present in unprotected form or may be protected forexample by one or more of the protecting groups mentioned hereinaboveunder “protecting groups”. The protecting groups are then wholly orpartly removed according to one of the methods described there.

In the conversion of an obtainable compound of formula (I) into anothercompound of formula (I), X with the meaning C═Y wherein Y is oxygen may,for example, be reacted with an optionally O-substituted hydroxylamineto give the corresponding oxime or oxime ether of formula (I) wherein Xis C═Y and Y is nitrogen substituted by hydroxy or alkoxy.

An obtainable compound of formula (I), wherein R¹ and/or R² is hydrogen,may be alkylated or acylated with a compound of formula R¹-Z or R²-Z,respectively, wherein Z is a nucleophilic leaving group as describedabove, to give a compound of formula (I), wherein R¹ and/or R² isdifferent from hydrogen. Preferred acylation conditions include the useof acid anhydrides and acid chlorides at elevated temperatures,typically in a range from approximately +30° C. to approximately +150°C. An acidic or basic catalyst may be employed if desired. A compound offormula (I) wherein R¹ and/or R² is alkyl may be obtained by alkylationof the parent compound of formula (I). Typical reaction conditionsallowing this transformation include the combination of a strong base,such as a metal hydride or a metal alcoholate and a compound of formulaR¹-Z or R²-Z.

Further amino groups present in an aryl or heteroaryl group R or in oneof the substitutents R³, R⁴, R⁵ or R⁶ may be transformed to othernitrogen containing substituents under conditions known in the art. Forexample, alkylation at nitrogen may be performed with an aldehyde underreducing conditions. For acylation the corresponding acyl chloride(Z=Cl) is preferred. Alternatively, an acid anhydride may be used, oracylation may be accomplished with the free acid (Z=OH) under conditionsused for amide formation known per se in peptide chemistry, e.g. withactivating agents for the carboxy group, such as 1-hydroxybenzotriazole,optionally in the presence of suitable catalysts or co-reagents.

Compounds of formula (I) wherein X═NOH may be alkylated allowing accessto the corresponding oxime ethers. The reaction conditions leading tothis transformation include combinations of weak bases and alkylatingagents. Typical bases include metal carbonates or bicarbonates.

Reduction of a nitro group in an nitro-substituted aryl or heteroarylgroup R or in one of the substituents R³, R⁴, R⁵ or R⁶ to give thecorresponding amino group is done, e.g., with iron powder in alcohol orwith other reducing agents.

A carboxy group in a carboxy-substituted aryl or heteroaryl group R orin one of the substituents R³, R⁴, R⁵ or R⁶ may be amidated underconditions used for amide formation known per se in peptide chemistry,e.g. with the corresponding amine and an activating agent for thecarboxy group, such as 1-hydroxybenzotriazole, optionally in thepresence of suitable catalysts or co-reagents.

A bromo or iodo substitutent in an aryl or heteroaryl group R or in oneof the substituents R³, R⁴, R⁵ or Re may be replaced by phenyl or aphenyl derivative by reaction with a suitable phenylboronic acid in aSuzuki reaction, preferably in a dipolar aprotic solvent such asdimethyl formamide, or in a polar ether, e.g. tetrahydrofuran ordimethoxyethane, in the presence of a soluble palladium(0) or relatedmetal catalyst, for example tetrakis-(triphenylphosphine)palladium.

Salts of a compound of formula (I) with a salt-forming group may beprepared in a manner known per se. Acid addition salts of compounds offormula (I) may thus be obtained by treatment with an acid or with asuitable anion exchange reagent.

Salts can usually be converted to free compounds, e.g. by treating withsuitable basic agents, for example with alkali metal carbonates, alkalimetal hydrogencarbonates, or alkali metal hydroxides, typicallypotassium carbonate or sodium hydroxide.

It should be emphasized that reactions analogous to the conversionsmentioned in this chapter may also take place at the level ofappropriate intermediates.

All process steps described here can be carried out under known reactionconditions, preferably under those specifically mentioned, in theabsence of or usually in the presence of solvents or diluents,preferably such as are inert to the reagents used and able to dissolvethese, in the absence or presence of catalysts, condensing agents orneutralising agents, for example ion exchangers, typically cationexchangers, for example in the H⁺ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from −100° C. to about 190° C., preferably fromabout −80° C. to about 150° C., for example at −80 to +60° C., at −20 to+40° C., at room temperature, or at the boiling point of the solventused, under atmospheric pressure or in a closed vessel, whereappropriate under pressure, and/or in an inert atmosphere, for exampleunder argon or nitrogen.

Salts may be present in all starting compounds and transients, if thesecontain salt-forming groups. Salts may also be present during thereaction of such compounds, provided the reaction is not therebydisturbed.

At all reaction stages, isomeric mixtures that occur can be separatedinto their individual isomers, e.g. diastereomers or enantiomers, orinto any mixtures of isomers, e.g. racemates or diastereomeric mixtures.

The invention relates also to those forms of the process in which onestarts from a compound obtainable at any stage as a transient andcarries out the missing steps, or breaks off the process at any stage,or forms a starting material under the reaction conditions, or uses saidstarting material in the form of a reactive derivative or salt, orproduces a compound obtainable by means of the process according to theinvention and further processes the said compound in situ. In thepreferred embodiment, one starts from those starting materials whichlead to the compounds described hereinabove as preferred, particularlyas especially preferred, primarily preferred, and/or preferred aboveall.

In the preferred embodiment, a compound of formula (I) is preparedaccording to or in analogy to the processes and process steps defined inthe Examples.

The compounds of formula (I), including their salts, are also obtainablein the form of hydrates, or their crystals can include for example thesolvent used for crystallization, i.e. be present as solvates.

New starting materials and/or intermediates, as well as processes forthe preparation thereof, are likewise the subject of this invention. Inthe preferred embodiment, such starting materials are used and reactionconditions so selected as to enable the preferred compounds to beobtained.

Starting materials of formula (II), (III), (IV) and (V) are known,commercially available, or can be synthesized in analogy to or accordingto methods that are known in the art.

Pharmaceutical Preparations, Methods, and Uses

The present invention relates also to pharmaceutical compositions thatcomprise a compound of formula (I) as active ingredient and that can beused especially in the treatment of the diseases mentioned at thebeginning. Compositions for enteral administration, such as nasal,buccal, rectal or, especially, oral administration, and for parenteraladministration, such as intravenous, intramuscular or subcutaneousadministration, to warm-blooded animals, especially humans, areespecially preferred. The compositions comprise the active ingredientalone or, preferably, together with a pharmaceutically acceptablecarrier. The dosage of the active ingredient depends upon the disease tobe treated and upon the species, its age, weight, and individualcondition, the individual pharmacokinetic data, and the mode ofadministration.

The present invention relates especially to pharmaceutical compositionsthat comprise a compound of formula (I), a tautomer, a prodrug or apharmaceutically acceptable salt, or a hydrate or solvate thereof, andat least one pharmaceutically acceptable carrier.

The invention relates also to pharmaceutical compositions for use in amethod for the prophylactic or especially therapeutic management of thehuman or animal body, in particular in a method of treating neoplasticdisease, autoimmune disease, transplantation related pathology and/ordegenerative disease, especially those mentioned hereinabove.

The invention relates also to processes and to the use of compounds offormula (I) thereof for the preparation of pharmaceutical preparationswhich comprise compounds of formula (I) as active component (activeingredient).

A pharmaceutical composition for the prophylactic or especiallytherapeutic management of a neoplastic disease, autoimmune disease,transplantation related pathology and/or degenerative disease, of awarm-blooded animal, especially a human or a commercially useful mammalrequiring such treatment, comprising a novel compound of formula (I) asactive ingredient in a quantity that is prophylactically or especiallytherapeutically active against the said diseases, is likewise preferred.

The pharmaceutical compositions comprise from approximately 1% toapproximately 95% active ingredient, single-dose administration formscomprising in the preferred embodiment from approximately 20% toapproximately 90% active ingredient and forms that are not ofsingle-dose type comprising in the preferred embodiment fromapproximately 5% to approximately 20% active ingredient. Unit dose formsare, for example, coated and uncoated tablets, ampoules, vials,suppositories, or capsules. Further dosage forms are, for example,ointments, creams, pastes, foams, tinctures, lip-sticks, drops, sprays,dispersions, etc. Examples are capsules containing from about 0.05 g toabout 1.0 g active ingredient.

The pharmaceutical compositions of the present invention are prepared ina manner known per se, for example by means of conventional mixing,granulating, coating, dissolving or lyophilizing processes.

Preference is given to the use of solutions of the active ingredient,and also suspensions or dispersions, especially isotonic aqueoussolutions, dispersions or suspensions which, for example in the case oflyophilized compositions comprising the active ingredient alone ortogether with a carrier, for example mannitol, can be made up beforeuse. The pharmaceutical compositions may be sterilized and/or maycomprise excipients, for example preservatives, stabilizers, wettingagents and/or emulsifiers, solubilizers, salts for regulating osmoticpressure and/or buffers and are prepared in a manner known per se, forexample by means of conventional dissolving and lyophilizing processes.The said solutions or suspensions may comprise viscosity-increasingagents, typically sodium carboxymethylcellulose, carboxymethylcellulose,dextran, polyvinylpyrrolidone, or gelatins, or also solubilizers, e.g.Tween 80® (polyoxyethylene(20)sorbitan mono-oleate).

Suspensions in oil comprise as the oil component the vegetable,synthetic, or semi-synthetic oils customary for injection purposes. Inrespect of such, special mention may be made of liquid fatty acid estersthat contain as the acid component a long-chained fatty acid having from8 to 22, especially from 12 to 22, carbon atoms. The alcohol componentof these fatty acid esters has a maximum of 6 carbon atoms and is amonovalent or polyvalent, for example a mono-, di- or trivalent,alcohol, especially glycol and glycerol. As mixtures of fatty acidesters, vegetable oils such as cottonseed oil, almond oil, olive oil,castor oil, sesame oil, soybean oil and groundnut oil are especiallyuseful.

The manufacture of injectable preparations is usually carried out understerile conditions, as is the filling, for example, into ampoules orvials, and the sealing of the containers.

Suitable carriers are especially fillers, such as sugars, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations,and/or calcium phosphates, for example tricalcium phosphate or calciumhydrogen phosphate, and also binders, such as starches, for examplecorn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone, and/or, if desired, disintegrators, such as theabove-mentioned starches, also carboxymethyl starch, crosslinkedpolyvinylpyrrolidone, alginic acid or a salt thereof, such as sodiumalginate. Additional excipients are especially flow conditioners andlubricants, for example silicic acid, talc, stearic acid or saltsthereof, such as magnesium or calcium stearate, and/or polyethyleneglycol, or derivatives thereof.

Tablet cores can be provided with suitable, optionally enteric, coatingsthrough the use of, inter alia, concentrated sugar solutions which maycomprise gum arabic, talc, polyvinyl-pyrrolidone, polyethylene glycoland/or titanium dioxide, or coating solutions in suitable organicsolvents or solvent mixtures, or, for the preparation of entericcoatings, solutions of suitable cellulose preparations, such asacetylcellulose phthalate or hydroxypropyl-methylcellulose phthalate.Dyes or pigments may be added to the tablets or tablet coatings, forexample for identification purposes or to indicate different doses ofactive ingredient.

Pharmaceutical compositions for oral administration also include hardcapsules consisting of gelatin, and also soft, sealed capsulesconsisting of gelatin and a plasticizer, such as glycerol or sorbitol.The hard capsules may contain the active ingredient in the form ofgranules, for example in admixture with fillers, such as corn starch,binders, and/or glidants, such as talc or magnesium stearate, andoptionally stabilizers. In soft capsules, the active ingredient ispreferably dissolved or suspended in suitable liquid excipients, such asfatty oils, paraffin oil or liquid polyethylene glycols or fatty acidesters of ethylene or propylene glycol, to which stabilizers anddetergents, for example of the polyoxyethylene sorbitan fatty acid estertype, may also be added.

Pharmaceutical compositions suitable for rectal administration are, forexample, suppositories that consist of a combination of the activeingredient and a suppository base. Suitable suppository bases are, forexample, natural or synthetic triglycerides, paraffin hydrocarbons,polyethylene glycols or higher alkanols.

For parenteral administration, aqueous solutions of an active ingredientin water-soluble form, for example of a water-soluble salt, or aqueousinjection suspensions that contain viscosity-increasing substances, forexample sodium carboxymethylcellulose, sorbitol and/or dextran, and, ifdesired, stabilizers, are especially suitable. The active ingredient,optionally together with excipients, can also be in the form of alyophilizate and can be made into a solution before parenteraladministration by the addition of suitable solvents.

Solutions such as are used, for example, for parenteral administrationcan also be employed as infusion solutions.

Preferred preservatives are, for example, antioxidants, such as ascorbicacid, or microbicides, such as sorbic acid or benzoic acid.

The present invention relates furthermore to a method for the treatmentof a neoplastic disease, autoimmune disease, transplantation relatedpathology and/or degenerative disease, which comprises administering acompound of formula (I) or a pharmaceutically acceptable salt thereof,wherein the radicals and symbols have the meanings as defined above forformula (I), in a quantity effective against said disease, to awarm-blooded animal requiring such treatment. The compounds of formula(I) can be administered as such or especially in the form ofpharmaceutical compositions, prophylactically or therapeutically,preferably in an amount effective against the said diseases, to awarm-blooded animal, for example a human, requiring such treatment. Inthe case of an individual having a bodyweight of about 70 kg the dailydose administered is from approximately 0.05 g to approximately 5 g,preferably from approximately 0.25 g to approximately 1.5 g, of acompound of the present invention.

The present invention relates especially also to the use of a compoundof formula (I), or a pharmaceutically acceptable salt thereof,especially a compound of formula (I) which is said to be preferred, or apharmaceutically acceptable salt thereof, as such or in the form of apharmaceutical formulation with at least one pharmaceutically acceptablecarrier for the therapeutic and also prophylactic management of one ormore of the diseases mentioned hereinabove, in particular a neoplasticdisease, autoimmune disease, transplantation related pathology and/ordegenerative disease.

The preferred dose quantity, composition, and preparation ofpharmaceutical formulations (medicines) which are to be used in eachcase are described above.

The following Examples serve to illustrate the invention withoutlimiting the invention in its scope.

EXAMPLES

Abbreviations: DMSO dimethyl sulfoxide; THF=tetrahydrofuran,DMAP=N,N-dimethylaminopyridine, DMF=N,N-dimethylformamide,DIPEA=N,N-diisopropyl-N-ethylamine.

Example 1 4-(1-Phenacyl-1H-benzimidazol-2-yl)-furazan-3-ylamine

Phenacylbromid (0.1 g, 0.49 mmol) is added to an efficiently stirredsuspension of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.1 g, 0.4mmol) [A. V. Sergievskii, O. A. Krasnoshek, S. F. Mel'nikova, I. V.Tselinskii, Russian Journal of Organic Chemistry, 2002, 38, 915-917] andpotassium carbonate (0.172 g, 1.24 mmol) in dry DMF (5 ml) at roomtemperature. After 4 hours the reaction mixture is diluted with ethylacetate and the organic phase is washed repeatedly with brine. Drying ofthe solvent, filtering and evaporation of the solvent under reducedpressure gives the title compound in crude form. The title compound isobtained in pure form by chromatography over silicagel, m.p. 202-204° C.

Example 2 4-[1-(4-Bromophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamineoxime

A mixture of4-[1-(4-bromophenacyl)-1H-benzimidazol-2-yl-furazan-3-ylamine (0.083 g,0.21 mmol, prepared according to Example 1), sodium bicarbonate (0.021g, 0.25 mmol) and hydroxylamine hydrochloride (0.014 g, 0.21 mmol) inethanol (5 ml) is refluxed for 20 hours. Partitioning of the reactionmixture between ethyl acetate and water, separation of the organic phasefollowed by drying and evaporation of the solvent gives the crudeproduct. Purification by chromatography on silicagel yields the titlecompound as an E/Z-mixture, m.p. 198-201° C.

Example 3Methyl-{4-[1-(4-chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl}-amine

A suspension of4-[1-(4-chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine (0.10 g,0.282 mmol, prepared according to Example 1), potassium carbonate (0.233g, 1.69 mmol) and dimethylsulfate (0.142 g, 1.12 mmol) in acetone (5 ml)is stirred at room temperature for 16 hours. Filtration of the solids,concentration of the filtrate under reduced pressure and chromatographyof the residue on silicagel using hexane-ethyl acetate as eluent givesthe title compound as a colorless solid, m.p. 210-214° C.

Example 4Dimethyl-{4-[1-(4-chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl}-amine

A suspension of4-[1-4-chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine (0.10 g,0.282 mmol), potassium carbonate (0.60 g, 4.22 mmol) and dimethylsulfate(0.50 g, 2.82 mmol) in DMF (5 ml) is stirred at 60° C. for 6 hours. Thereaction mixture is diluted with ethyl acetate, washed with water anddried over sodium sulphate. Filtration of the sodium sulphate,concentration of the filtrate under reduced pressure and chromatographyof the residue on silicagel using hexane-ethyl acetate as eluent givesthe title compound as a yellowish solid, m.p. 120-123° C.

Example 5N-{4-[1-(4-Chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl}-acetamide

A solution of4-[1-(4-chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine (0.05 g,0.143 mmol), pyridine (0.022 g, 0.282 mmol), acetyl chloride (0.013 g,0.169 mmol) and a catalytic amount of DMAP in DMF (5 ml) is stirred at80° C. for 16 hours. The reaction mixture is diluted with ethyl acetate,washed with water and dried over sodium sulphate. Filtration of thesodium sulphate, concentration of the filtrate under reduced pressureand chromatography of the residue on silicagel using hexane-ethylacetate as eluent gives the title compound as a yellowish solid, m.p.202-205° C.

Example 64-[1-(4-Chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine

A suspension of4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(2-cyanoethyl)-amine (0.10 g,0.39 mmol), potassium carbonate (0.08 g, 0.58 mmol) and 4-chlorophenacylbromide (0.11 g, 0.47 mmol) in DMF (5 ml) is stirred at room temperaturefor 16 hours. The reaction mixture is diluted with ethyl acetate, washedwith water and dried over sodium sulphate. Filtration of the sodiumsulphate, concentration of the filtrate under reduced pressure andchromatography of the residue on silicagel using hexane-ethyl acetate aseluent gives the title compound as a yellowish solid, m.p. 191-192° C.

Example 6a 4-(1H-Benzimidazol-2-yl)-furazan-3-yl-N-(2-cyanoethyl)-amine

To a solution of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.10 g,0.497 mmol) in pyridine (5 ml) sodium in methanol (0.02 g, 0.86 mmol in1 ml) and acrylonitrile (0.03 g, 0.39 mmol) are added sequentially at 0°C. The mixture is stirred over night. Evaporation of the solvent underreduced pressure and partitioning of the resulting residue between waterand ethyl acetate followed by drying of the organic solution over sodiumsulphate gives the title compound in pure form. ¹H-NMR (400 MHz,d⁶-DMSO): 13.7 (s, 1H); 7.82 (d, 1H); 7.60 (d, 1H); 7.36 (m, 2H); 7.20(t, 1H); 3.67 (q, 2H); 2.94 (t, 2H).

Example 7 4-(1-Phenoxymethyl-1H-benzimidazol-2-yl-furazan-3-ylamine

To a solution of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.10 g,0.497 mmol) is added potassium carbonate (0.172 g, 1.24 mmol) andiodomethoxy benzene (0.128 g, 0.546 mmol). The mixture is stirred overnight. Evaporation of the solvent under reduced pressure andpartitioning of the resulting residue between water and ethyl acetatefollowed by drying of the organic solution over sodium sulphate andchromatography of the residue gives the title compound as a colorlesssolid, m.p. 171-173° C.

Example 84-[1-(4-Fluorophenoxymethyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine

To a solution of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.10 g,0.497 mmol) is added potassium carbonate (0.172 g, 1.24 mmol) followedby 4-fluorophenol (0.0557 g, 0.497 mmol) and diiodomethane (0.133 g,0.497 mmol). The mixture is stirred over night. Evaporation of thesolvent under reduced pressure and partitioning of the resulting residuebetween water and ethyl acetate followed by drying of the organicsolution over sodium sulphate and chromatography of the residue givesthe title compound as a colorless solid, m.p. 155-158° C.

Example 94-[1-(4-Chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-methoxycarbonylethyl)-amine

A suspension of4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(2-methoxycarbonylethyl)-amine(0.052 g, 0.181 mmol), potassium carbonate (0.062 g, 0.452 mmol) and4-chlorophenacyl bromide (0.047 g, 0.199 mmol) in DMF (5 ml) is stirredat room temperature for 16 hours. The reaction mixture is diluted withethyl acetate, washed with water and dried over sodium sulphate.Filtration of the sodium sulphate, concentration of the filtrate underreduced pressure and chromatography of the residue on silicagel usinghexane-ethyl acetate as eluent gives the title compound as hygroscopicsolid of undefined melting point. ¹H-NMR (400 MHz, d⁶-DMSO): 8.14 (d,2H); 7.87 (m, 2H); 7.41 (m, 2H); 7.32 (d, 2H); 7.29 (t, 1H); 6.37 (s,2H); 3.63 (m, 2H); 3.61 (s, 3H); 2.76 (t, 2H).

Example 9a4-[1-(1H-Benzimidazol-2-yl]-furazan-3-yl-N-(2-methoxycarbonylethyl)-amine

A solution of4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(2-cyanoethyl)-amine (0.05 g,Example 6a) in methanol saturated with hydrochloric acid (5 ml) isheated at reflux for 40 minutes. After addition of a drop of waterrefluxing is continued for 2 hours. The mixture is neutralized usingsodium bicarbonate and then extracted repeatedly using ethyl acetate.The combined organic extracts are dried and evaporated to dryness underreduced pressure. Trituration with hexane and filtering yields the titlecompound in pure form. ¹H-NMR (400 MHz, d⁶-DMSO): 13.8 (s, 1H); 7.80 (m,1H); 7.59 (m, 1H); 7.32 (m, 2H); 7.03 (m, 1H); 3.63 (m, 2H); 3.61 (s,3H); 2.76 (t, 2H).

Example 104-[1-(3,4-Dimethylphenoxymethyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine

A suspension of4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(2-cyanoethyl)-amine (0.15 g,0.59 mmol, Example 6a), potassium carbonate (0.325 g, 2.36 mmol),diiodomethane (0.16 g, 0.59 mmol) and 3,4-dimethylphenol (0.072 g, 0.59mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. Thereaction mixture is diluted with ethyl acetate, washed with water anddried over sodium sulphate. Filtration of the sodium sulphate,concentration of the filtrate under reduced pressure and chromatographyof the residue on silicagel using hexane-ethyl acetate as eluent givesthe title compound as a yellowish solid, m.p. 132-135° C.

Example 114-[1-(4-Chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(3-hydroxypropyl)-amine

A suspension of4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(3-hydroxypropyl)-amine (0.70 g,0.27 mmol), potassium carbonate (0.472 g, 3.42 mmol) and4-chlorophenacyl bromide (0.069 g, 0.29 mmol) in DMF (5 ml) is stirredat room temperature for 16 hours. The reaction mixture is diluted withethyl acetate, washed with water and dried over sodium sulphate.Filtration of the sodium sulphate, concentration of the filtrate underreduced pressure and chromatography of the residue on silicagel usinghexane-ethyl acetate as eluent gives the title compound as a yellowishsolid, m.p. 166-169° C.

Example 11a4-(1H-Benzimidazol-2-yl)-furazan-3-yl-N-(3-hydroxypropyl)-amine

A solution of4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(2-cyanoethyl)-amine (0.272 g,0.947 mmol, Example 6a) in THF (5 ml) is added dropwise at 0° C. to anefficiently stirred suspension of LiAlH₄ (0.054 g, 1.42 mmol) in THF (5ml). After stirring for 16 hours at room temperature the mixture isquenched by careful addition of aqueous saturated solution of sodiumsulphate. The suspension is filtered and the filtrate evaporated todryness. Crystallization by addition of hexane yields the title compoundin pure form. ¹H-NMR (400 MHz, d⁶-DMSO): 13.6 (s, 1H); 7.66 (m, 2H);7.31 (m, 2H); 6.92 (t, 1H); 4.61 (m, 1H); 3.51 (m, 2H); 3.39 (m, 2H);1.81 (m, 2H).

Example 12E-1-[2-(4-Aminofurazan-3-yl)-benzimidazol-1-yl]-4-phenyl-but-3-en-2-one

A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.275 g,1.37 mmol), potassium carbonate (0.472 g, 3.42 mmol) and1-chloro-4-phenyl-but-3-en-2-one (0.297 g, 1.64 mmol) in DMF (5 ml) isstirred at room temperature for 16 hours. The reaction mixture isdiluted with ethyl acetate, washed with water and dried over sodiumsulphate. Filtration of the sodium sulphate, concentration of thefiltrate under reduced pressure and chromatography of the residue onsilicagel using hexane-ethyl acetate as eluent gives the title compoundas a yellowish solid, m.p. 176-180° C.

Example 12a 1-Chloro-4-phenyl-but-3-en-2-one

A mixture of 1-chloro-3-(triphenylphosphanylidene)-propane-2-one (2.8 g,7.9 mmol) and freshly distilled benzaldehyde (0.7 g, 6.6 mmol) intoluene (10 ml) is heated at reflux for 20 hours. Evaporation to drynessyields a mixture containing the title compound that is used in thesubsequent step without purification.

Example 12b 1-Chloro-3-(triphenylphosohanylidene)-propane-2-one

A mixture of triphenylphosphine (10.0 g, 38.1 mmol) and1,3-dichloroacetone (4.84 g, 38.1 mmol) in THF (20 ml) is heated atreflux for 4 hours. On cooling the resulting precipitate is filtered,washed with THF and dried. To the efficiently stirred precipitate inmethanol (20 ml) a 20% aqueous solution of sodium carbonate (2.02 g, 19mmol) is added followed by additional water. The resulting product isfiltered and dried to yield the pure product. ¹H-NMR (400 MHz, d⁶-DMSO):7.61 (m, 15H); 4.07 (2s, 0.5H each); 3.98 (s, 2H).

Example 134-[1-(4-Aminophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-carboxyethyl)-amine

A solution of4-[1-(4-acetaminophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine(0.061 g) in aqueous hydrochloric acid (5 ml, HCl conc.) is heated atreflux for two hours. The mixture is diluted with water and neutralizedby addition of sodium bicarbonate. Extraction with ethyl acetate, dryingover sodium sulphate, filtering and evaporation of the resultingfiltrate to dryness gives the title compound in pure form, m.p. 174-177°C. ¹H-NMR (400 MHz, d⁶-DMSO): 12.40 (s, 1H); 7.84 (m, 4H); 7.38 (m, 3H);6.65 (m, 2H); 6.28 (S, 2H); 6.17 (s, 2H); 3.57 (m, 2H); 2.66 (t, 2H).

Example 144-[1-(3-Amino-4-chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine

To a stirred solution of4-[1-(4-chloro-3-nitrophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine(0.07 g, 0.175 mmol) in ethanol (6 ml) and water (1 ml) is added twodrops of concentrated hydrochloric acid and iron powder (0.1 g, 17.5mmol). The reaction mixture is heated at 80° C. for 8 hours. Filtrationand evaporation at reduced pressure gives the crude product.Purification by extraction with ethyl acetate and chromatography onsilicagel yields the title compound as colorless solid, m.p. 228-230° C.

Example 14a4-[1-(4-Chloro-3-nitrophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine

A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.228 g,1.14 mmol), potassium carbonate (0.40 g, 2.85 mmol) and4-chloro-3-nitrophenacyl bromide (0.35 g, 1.25 mmol) in DMF (5 ml) isstirred at room temperature for 16 hours. The reaction mixture isdiluted with ethyl acetate, washed with water and dried over sodiumsulphate. Filtration of the sodium sulphate, concentration of thefiltrate under reduced pressure and chromatography of the residue onsilicagel using hexane-ethyl acetate as eluent gives the title compoundas a solid, m.p. 198-200° C. (This compound is also listed as Example 66in Table 1.)

Example 154-[1-(3-Methoxy-4-methoxymethoxy-phenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine

A mixture of4-1-(3-methoxy-4-hydroxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine(0.10 g, 0.27 mmol), DIPEA and methoxymethyl chloride in dry DMF isstirred at room temperature for 14 hours. The reaction mixture isdiluted with ethyl acetate, washed with water and dried over sodiumsulphate. Filtration of the sodium sulphate and concentration of thefiltrate under reduced pressure gives the title compound as colorless,pure solid, m.p. 190° C.

Example 15a4-[1-(3-Methoxy-4-hydroxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-amine

To a solution of4-[1-(3-methoxy-4-benzyloxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine(1.00 g) in THF (20 ml) is added palladium on carbon (10%, 0.2 g). Themixture is stirred under a hydrogen atmosphere for 1 hour. The catalystis filtered and the filtrate is evaporated to dryness to give the titlecompound in pure form, m.p. 265° C. (This compound is also listed asExample 74 in Table 1.)

The following compounds are prepared in analogy to Examples 1-15: TABLE1

Ex R Y R¹ Salt Comment m.p. 16

O H — 198-200° C. 17

NOH H — E/Z 210° C. 18

NOMe H — E/Z 156-158° C. 19

O H — 160-162° C. 20

NOH H — E/Z 176-178° C. 21

NOH H — E/Z 204-206° C. 22

NOMe H — E/Z 206-208° C. 23

O H — 181-184° C. 24

NOH H — E/Z 189-192° C. 25

NOMe H — E/Z 160° C. 26

O H — 226-228° C. 27

NOH H — E/Z 196-198° C. 28

NOMe H — E/Z 164-166° C. 29

O H — 212-214° C. 30

NOMe H — E/Z 150-154° C. 31

O H — 200-201° C. 32

O H — 207-209° C. 33

NOH H — E/Z 160-163° C. 34

NOMe H — E/Z 138-140° C. 35

O H — 192-194° C. 36

NOH H — E/Z 188-190° C. 37

NOMe H — E/Z 125-127° C. 38

NOMe H — E/Z 110-113° C. 39

O H — 202° C. 40

O Ac — 226° C. 41

O H — 226° C. 42

O H — 180-183° C. 43

O H — 215-218° C. 44

O H — 206-209° C. 45

O H — 211-214° C. 46

O CH₂CH₂CN — 180-182° C. 47

O CH₂CH₂CN — 204° C. 48

O CH₂CH₂CN — 210° C. 49

O H — 224-227° C. 50

O H — 92-96° C. 51

O H HCl 227-230° C. 52

O CH₂CH₂CH₂OH — 160-162° C. 53

O H — 191-194° C. 54

O CH₂CH₂CN — 175-178° C. 55

O H — 208-210° C. 56

O CH₂CH₂CN — 180-183° C. 57

O CH₂CH₂CN — 178-181° C. 58

O CH₂CH₂CN — 196-199° C. 59

O H — 179° C. 60

O H — 250° C. 61

O CH₂CH₂CN (COOH)₂ 137-140° C. 62

O H (COOH)₂ 148-150° C. 63

O H — 242-246° C. 64

O H — 250-252° C. 65

O H — >250° C.   66

O H — 198-200° C. 67

O H — 218-220° C. 68

O H — 220-223° C. 69

O CH₂CH₂CN — 225-226° C. 70

O H — 190-192° C. 71

O H — 186-188° C. 72

O H — 205° C. 73

O H — 208-210° C. 74

O H — 265° C. 75

O H — 205-208° C. 76

O H — 244° C. 77

O H — 174° C. 78

O H — >250° C.   79

O CH₂CH₂CN — 223° C. 80

O CH₂CH₂CN — 81

O H — 250° C. 82

O CH₂CH₂CN — 83

O H — oil 84

O CH₂CH₂CN — 85

O CH₂CH₂CN HCl 86

O CH₂CH₂CN — 87

O CH₂CH₂CN HCl

TABLE 2

Ex R R¹ Salt Comment m.p. 88

H — 162-165° C. 89

H — 164-167° C. 90

H — 156-159° C. 91

H — 148-150° C. 92

H — 151-153° C. 93

CH₂CH₂CN — 162-165° C. 94

CH₂CH₂CN — 176-179° C. 95

CH₂CH₂CN — 175-178° C. 96

H — 193-196° C. 97

H — 98

H — 190-193° C. 99

H — 110-113° C. 100

H HCl 251-252° C. 101

H — 142-145° C. 102

H — 155-158° C. 103

H — 145-148° C. 104

CH₂CH₂CN — 105

CH₂CH₂CH₂OH — 106

H — 107

H —

TABLE 3

Com- Ex R R⁴ R⁵ Salt ment m.p. 108

Me Me — 250° C. 109

Me Me — 238° C. 110

Me Me — 237° C. 111

Me Me — 218-220° C. 112

Me Me — 228° C. 113

OMe OMe — >250° C.   114

OMe OMe — >250° C.   115

OMe OMe — >250° C.   116

OMe OMe — >250° C.   117

OMe OMe — 238° C.

TABLE 4

Ex R Salt Comment m.p. 118

— E 194-196° C. 119

— E 188-192° C. 120

— E 194-195° C.

The following compounds from WO 03/066629 are prepared for comparison oftheir activity in analogy to the examples described hereinbefore: TABLE5

Ex R MH⁺ A

244 B

256General methods for testing of compounds of the invention:

Example 121 Cell Cultures and Cell Lines

Cell lines are cultured in RPMI-1640 tissue culture medium containingeither 5% or 10% fetal calf serum, 0.05 mM 2-mercaptoethanol, 2 mMglutamine and penicillin/streptomycin 50 μg/ml (complete medium) (Sigma,Buchs, Switzerland). General growth conditions are 37° C. and 7.5% CO₂.

The following mouse cell lines (either EGFP transfected or not) arebeing used: A20.2J (ATCC: TIB-208), MC57G (ATCC: CRL-2295).

The following human cell lines (either EGFP transfected or not) arebeing used: HeLa (ATCC: CCL-2), KB (ATCC: CCL-17), MCF7 (ATCC: HTB-22),SK-BR-3 (ATCC: HTB-30), SK-Mel 1 (ATCC: HTB-67), SK-Mel 28 (ATCC:HTB-72), PC-3 (ATCC: CRL-1435), SW 480 (ATCC: CCL-228), NCl-H460 (ATCC:HTB-177), NCl-H1792 (ATCC: CRL-5895), HT1080 (ATCC: CCL-21), Jurkat(ATCC: TIB-152), Ramos (ATCC: CRL-1596), Raji (ATCC: CCL-86), H9 (ATCC:HTB-176), Hut78 (ATCC: TIB-161), K562 (ATCC: CCL 243), HL-60 (ATCC: CCL240), U-87MG (ATCC: HTB-14), HepG2 (ATCC: HB-8065), U-2 OS (ATCC:HTB-96), Saos-2 (ATCC: HTB-85), U937 (ATCC: CRL 1593), Hs 578T (ATCC:HTB 126), HBL-100 (ATCC: HTB 124), Molt-4 (ATCC: CRL 1582).

Example 122 Primary Screening Setup

All the manipulations are performed under sterile conditions. The assaysare being performed in commercially available 96 or 384 well flat bottomclear microtiter plates (Greiner, Germany) respectively, which aresuitable for tissue culture techniques. A defined number of EGFPtransfected adherent test cells (96 well plates: 10⁴-10⁵, 384 wellplates: 1500-2*10⁴) are plated out 24 hours before treatment either in75 μl (96 well plates) or 60 μl (384 well plates) complete medium perwell in order to ensure appropriate cell spreading. For this purpose aperistaltic pump (e.g. Multidrop by Thermo-Labsystems, Finland) oranother suitable device is used. Cells in suspension are plated outaccording to the same procedure but 1 h prior to treatment. Betweenseeding out and treatment or addition of compounds the cells areincubated at 37° C. under 7.5% CO₂. Subsequently, the compounds underinvestigation are added at defined concentrations (40-80 μM in either 25μl (96 well plates) or 20 μl (384 well plates) complete mediumcontaining max 4% DMSO) with an appropriate device (e.g. liquid handlingsystem, multi channel pipette etc.) resulting in a final concentrationin the test well of 10-20 μM compound in max 1% DMSO.

Immediately after the addition of the compounds to the cells the zerofluorescence value (t=0 h) is determined by using a fluorescencemicroplate reader in order to be able to normalize the fluorescenceactivities. Afterwards, the test plates are further incubated for atotal of 48 h at 37° C. under 7.5% CO₂ and are shortly removed only forthe purpose of measurement at 8 h, 24 h and 48 h, respectively.

Example 123 Measurement and Quantification of the Primary Screening

Relative fluorescence activities of EGFP in compound treated test cellsin relation to control cells and cells treated with standard drugs aremeasured by using a BMG Fluostar microplate fluorescence reader equippedwith a filter pair for excitation/emission at 485 nm/520 nm. The optimumsignal to noise ratio is detected by using the time-resolved mode ofmeasurement with a delay of 20 μs and an integration time over 1 ms. Thegain is adjusted in such a way that the control cells produce afluorescence activity of 90% of the maximum. Kinetics is performed bymeasuring the relative fluorescence activities at t=0 h, 8 h, 24 h and48 h. Crude fluorescence activities are individually normalized fordifferent cell numbers and various optical activities of the testcompounds/plate-wells by dividing each value from t=8 h, 24 h and 48 hby the value of t=0 h resulting in E(8), E(24) and E(48) values.Subsequently, the E(x) values are further processed by forming theinverse (Q-value) of the products E(8)*E(24)*E(48) which result innumbers >1 for apoptotic/necrotic activities of the compounds andnumbers <1 for proliferative activities of the compounds. Controls(untreated) show values similar to 1. Compounds producing Q values >2are being considered relevant in terms of apoptotic/necrotic activityand are subsequently tested in the secondary screening setup.

Example 124 Secondary Screening Setup

All the manipulations are performed under sterile conditions. The assaysare being performed in case of adherent cells in commercially available24 well flat bottom tissue culture plates (Greiner, Germany) and in caseof suspension cells in polypropylene tubes (P-tubes) 1.4 ml (Matrix,UK), respectively.

Adherent test cells: 2*10⁴-4*10⁴ of EGFP transfected cells in 0.5 mlcomplete medium are plated out 24 h before treatment. At t=0 the mediumis removed and 450 μl new complete medium is added. Subsequently, 50 μlcomplete medium containing the test compound in max. 5% DMSO is addedresulting in final concentrations of 20 μM, 10 μM, 3 μM, 1 μM and 0.3 μMof the test compounds, respectively. After 48 h incubation the cells areharvested and analyzed with fluorescence activated cell scanning device(FACS Calibur™, BD Biosciences) according to standard procedures.

Suspension cells: 10⁵ test cells in 450 μl complete medium are pipettedinto P-tubes. 50 μl complete medium containing the compounds (seeadherent cells) is added immediately. After 48 h of incubation the testcells are analyzed directly on a FACSCalibur™.

Example 125 Quantification of the Secondary Screening

By monitoring the EGFP fluorescence activity in FL1 on a FACSCalibur™,it is possible to distinguish between proliferating cells, apoptoticcells and necrotic cells within the same cell population. Theproliferating cells show a high GFP fluorescence activity, the apoptoticpopulation shows an intermediate fluorescence activity whereas thenecrotic cells demonstrate a residual fluorescence activity comparableto mock-transfected cells. Within the CellQuest Software (BDBiosciences) three regions are defined in the histogram: M1 comprisingthe proliferating cells, M2 comprising the apoptotic cell population andM3 comprising the necrotic cell population. As readout the relativeabundance of the cells belonging either to M1, M2 or M3 are expressed.Compounds inducing M2 values >50% and M3 values <30% are beingconsidered relevant and are further tested and characterized in thetertiary/advanced screening setup.

Example 126 Tertiary Screening Setup

A) Hoechst 33342 Nuclear Staining

This assay is performed in 96 well tissue culture plates. Appropriatenumber of cells (adherent cells: 3-5*10³, suspension cells: 8-10*10³)are being seeded out in 80 μl complete medium. Adherent cells areincubated for 24 h for proper spreading out before addition of testcompounds while suspension cells are immediately treated with testcompounds after seeding out. The test compounds are added in 20 μlcomplete medium containing max 5% DMSO. The final compoundconcentrations in the assays are 10 μM, 3 μM, 1 μM and 0.3 μM,respectively. After 24 h or 48 h incubation at culture conditions, 10 μlmedium containing Hoechst 33342 dye (Sigma B-2261) at 2-5 μg/ml areadded to each well. The assay plates are then further incubated for 30minutes and subsequently analyzed with a standard inverted fluorescencemicroscope.

The readout allows the determination of the fraction of apoptotic nucleias well as other morphological criteria specific for apoptosis as afunction of the treatment. Results are indicated in Table 6. Thefollowing scores are used: 0 relating to no activity, 1 relating to weakactivity comprising less than 70% of the cells and score 2 relating tostrong activity comprising more than 70% of the cells. TABLE 6 Hoechst33342 nuclear staining Example conc Jurkat Jily PBLs HeLa H460 MRC5  1 1μM 2 n.d. 0 2 2 1 0.1 μM 0 n.d. 0 0 0 0 0.01 μM 0 n.d. 0 0 0 0  2 1 μM 0n.d. 0 0 0 0 0.1 μM 0 n.d. 0 0 0 0 0.01 μM 0 n.d. 0 0 0 0  3 1 μM 0 n.d.0 0 n.d. 0 0.1 μM 0 n.d. 0 0 n.d. 0 0.01 μM 0 n.d. 0 0 n.d. 0  4 1 μM 22 0 2 1 2 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0  5 1 μM 2 n.d. 0 2 n.d.0 0.1 μM 0 n.d. 0 0 n.d. 0 0.01 μM 0 n.d. 0 0 n.d. 0  6 1 μM 2 2 0 2 2 20.1 μM 2 2 0 2 2 2 0.01 μM 2 2 0 0 0 2  7 1 μM 2 2 0 2 2 0 0.1 μM 0 0 00 0 0 0.01 μM 0 0 0 0 0 0  8 1 μM 1 0 0 1 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM0 0 0 0 0 0  9 1 μM 2 2 2 2 0 2 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 010 1 μM 2 2 0 2 2 1 0.1 μM 2 1 0 0 1 0 0.01 μM 0 0 0 0 0 0 11 1 μM 2 2 02 2 2 0.1 μM 2 2 0 1 0 1 0.01 μM 0 0 0 0 0 0 12 1 μM 2 2 0 0 0 0 0.1 μM0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 13 1 μM 2 2 0 2 2 2 0.1 μM 0 0 0 0 0 00.01 μM 0 0 0 0 0 0 14 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 1 2 1 0.01 μM 0 0 00 0 0 15 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 2 2 1 0.01 μM 2 2 0 1 2 0 16 1 μM2 2 0 2 2 2 0.1 μM 2 2 0 2 2 2 0.01 μM 0 0 0 0 0 0 17 1 μM 0 0 0 0 0 00.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 18 1 μM 2 n.d. 0 2 1 1 0.1 μM 0n.d 0 0 0 0 0.01 μM 0 n.d 0 0 0 0 19 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 1 0 00.01 μM 0 0 0 0 0 0 20 1 μM 0 n.d. 0 0 0 0 0.1 μM 0 n.d 0 0 0 0 0.01 μM0 n.d 0 0 0 0 21 1 μM 0 n.d. 0 0 0 0 0.1 μM 0 n.d 0 0 0 0 0.01 μM 0 n.d0 0 0 0 22 1 μM 2 n.d. 0 2 0 0 0.1 μM 0 n.d 0 0 0 0 0.01 μM 0 n.d 0 0 00 23 1 μM 2 n.d. 0 2 n.d. 0 0.1 μM 0 n.d 0 0 n.d 0 0.01 μM 0 n.d 0 0 n.d0 24 1 μM 0 0 0 0 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 25 1 μM 1 00 0 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 26 1 μM 0 0 0 0 0 0 0.1μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 27 1 μM 0 n.d. 0 0 0 0 0.1 μM 0 n.d.0 0 0 0 0.01 μM 0 n.d. 0 0 0 0 28 1 μM 0 0 0 0 0 0 0.1 μM 0 0 0 0 0 00.01 μM 0 0 0 0 0 0 29 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 1 0 2 0.01 μM 0 0 00 0 0 30 1 μM 2 1 0 1 0 2 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 31 1 μM1 n.d. 0 0 0 0 0.1 μM 0 n.d. 0 0 0 0 0.01 μM 0 n.d. 0 0 0 0 32 1 μM 2 00 0 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 33 1 μM 0 0 0 0 0 0 0.1μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 34 1 μM 0 0 0 0 0 0 0.1 μM 0 0 0 0 00 0.01 μM 0 0 0 0 0 0 35 1 μM 2 2 0 2 2 2 0.1 μM 2 1 0 0 0 2 0.01 μM 0 00 0 0 0 36 1 μM n.d. 0 0 0 0 0 0.1 μM n.d. 0 0 0 0 0 0.01 μM n.d. 0 0 00 0 37 1 μM n.d. 2 0 0 0 1 0.1 μM n.d. 0 0 0 0 0 0.01 μM n.d. 0 0 0 0 038 1 μM 0 0 0 0 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 39 1 μM 0 0 00 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 40 1 μM 0 1 0 0 0 0 0.1 μM0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 41 1 μM 2 2 1 2 n.d. 0 0.1 μM 0 0 0 0n.d. 0 0.01 μM 0 0 0 0 n.d. 0 42 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 1 2 20.01 μM 0 0 0 0 0 0 43 1 μM 2 1 0 1 n.d. 1 0.1 μM 0 0 0 0 n.d. 0 0.01 μM0 0 0 0 n.d. 0 44 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 1 2 0 0.01 μM 0 0 0 0 00 45 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 1 2 0 0.01 μM 0 0 0 0 0 0 46 1 μM 2 20 2 2 2 0.1 μM 2 2 0 0 0 0 0.01 μM 0 0 0 0 0 0 47 1 μM 2 2 0 2 2 2 0.1μM 2 2 0 2 2 2 0.01 μM 2 0 0 0 0 0 48 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 2 02 0.01 μM 0 0 0 0 0 0 49 1 μM 2 1 0 1 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 00 0 0 0 50 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 2 2 2 0.01 μM 2 2 0 0 1 0 51 1μM 2 2 0 2 2 2 0.1 μM 2 2 0 2 2 2 0.01 μM 1 0 0 0 0 0 52 1 μM 2 2 0 2 22 0.1 μM 2 2 0 2 1 2 0.01 μM 0 0 0 0 0 0 53 1 μM 2 2 0 2 2 2 0.1 μM 2 20 2 2 2 0.01 μM 2 0 0 0 0 1 54 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 2 2 2 0.01μM 1 1 0 0 0 0 55 1 μM 2 2 0 2 2 0 0.1 μM 1 0 0 0 0 0 0.01 μM 0 0 0 0 00 56 1 μM 2 2 0 2 2 1 0.1 μM 2 2 0 1 0 1 0.01 μM 0 0 0 0 0 0 57 1 μM 2 20 2 0 2 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 58 1 μM 2 2 0 2 2 2 0.1μM 2 2 0 2 2 2 0.01 μM 2 2 0 2 2 1 59 1 μM 2 2 0 2 2 2 0.1 μM 0 0 0 0 00 0.01 μM 0 0 0 0 0 0 60 1 μM 2 2 0 1 0 2 0.1 μM 0 0 0 0 0 0 0.01 μM 0 00 0 0 0 61 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 2 2 2 0.01 μM 0 0 0 0 0 0 62 1μM 2 2 0 2 2 2 0.1 μM 2 2 0 2 2 2 0.01 μM 0 0 0 0 0 0 63 1 μM 0 0 0 0 00 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 64 1 μM 2 2 0 2 2 1 0.1 μM 2 20 2 2 1 0.01 μM 2 2 0 0 0 0 65 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 2 2 2 0.01μM 2 2 0 0 2 0 66 1 μM 2 2 0 2 2 1 0.1 μM 1 0 0 0 0 0 0.01 μM 0 0 0 0 00 67 1 μM 2 2 0 2 2 1 0.1 μM 2 2 0 0 0 0 0.01 μM 0 0 0 0 0 0 68 1 μM 2 10 2 2 1 0.1 μM 2 1 0 0 0 0 0.01 μM 0 0 0 0 0 0 69 1 μM 2 2 0 2 2 1 0.1μM 1 1 0 0 0 0 0.01 μM 0 0 0 0 0 0 70 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 2 22 0.01 μM 2 2 0 0 1 1 71 1 μM 2 1 0 0 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 00 0 0 0 72 1 μM 2 2 0 2 2 0 0.1 μM 1 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 73 1μM 2 1 0 1 2 1 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 74 1 μM 2 2 0 2 21 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 75 1 μM 2 2 0 1 2 1 0.1 μM 0 00 0 0 0 0.01 μM 0 0 0 0 0 0 76 1 μM 2 2 0 2 2 1 0.1 μM 2 2 0 0 1 0 0.01μM 0 0 0 0 0 0 77 1 μM 2 2 0 2 2 1 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 00 78 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 2 2 2 0.01 μM 2 2 0 2 2 1 79 1 μM 2 20 2 2 2 0.1 μM 2 2 0 2 2 2 0.01 μM 2 2 0 2 2 1 80 1 μM 0.1 μM 0.01 μM 811 μM 0.1 μM 0.01 μM 82 1 μM 0.1 μM 0.01 μM 83 1 μM 0.1 μM 0.01 μM 84 1μM 0.1 μM 0.01 μM 85 1 μM 0.1 μM 0.01 μM 86 1 μM 0.1 μM 0.01 μM 87 1 μM0.1 μM 0.01 μM 88 1 μM 2 1 0 2 n.d. 0 0.1 μM 0 0 0 0 n.d. 0 0.01 μM 0 00 0 n.d. 0 89 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 2 2 2 0.01 μM 0 0 0 0 0 0 901 μM 2 1 0 1 n.d. 1 0.1 μM 0 0 0 0 n.d. 0 0.01 μM 0 0 0 0 n.d. 0 91 1 μM2 2 0 0 n.d. 0 0.1 μM 0 0 0 0 n.d. 0 0.01 μM 0 0 0 0 n.d. 0 92 1 μM 2 20 2 2 2 0.1 μM 2 2 0 2 2 2 0.01 μM 0 0 0 0 0 0 93 1 μM 2 2 0 2 2 2 0.1μM 2 2 0 0 1 0 0.01 μM 0 0 0 0 0 0 94 1 μM 2 2 0 2 2 2 0.1 μM 2 2 0 1 20 0.01 μM 0 0 0 0 0 0 95 1 μM 2 1 0 1 n.d. 0 0.1 μM 0 0 0 0 n.d. 0 0.01μM 0 0 0 0 n.d. 0 96 1 μM 2 2 0 2 1 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 00 0 97 1 μM 2 2 0 2 2 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 98 1 μM 22 0 0 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 99 1 μM 1 1 0 0 0 0 0.1μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 100  1 μM 1 1 0 0 0 0 0.1 μM 0 0 0 00 0 0.01 μM 0 0 0 0 0 0 101  1 μM 2 2 0 2 2 1 0.1 μM 2 1 0 1 1 1 0.01 μM0 0 0 0 0 0 102  1 μM 2 1 0 0 1 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0103  1 μM 2 2 0 2 2 1 0.1 μM 1 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 104  1 μM0.1 μM 0.01 μM 105  1 μM 0.1 μM 0.01 μM 106  1 μM 0.1 μM 0.01 μM 107  1μM 0.1 μM 0.01 μM 108  1 μM 2 2 0 0 1 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 00 0 0 109  1 μM 0 0 0 0 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 110 1 μM 0 0 0 0 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 111  1 μM 0 0 00 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 112  1 μM 0 0 0 0 0 0 0.1μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 113  1 μM 0 0 0 0 0 0 0.1 μM 0 0 0 00 0 0.01 μM 0 0 0 0 0 0 114  1 μM 0 0 0 0 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM0 0 0 0 0 0 115  1 μM 0 0 0 0 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0116  1 μM 0 0 0 0 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 117  1 μM 00 0 0 0 0 0.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 118  1 μM 0 1 0 0 0 00.1 μM 0 0 0 0 0 0 0.01 μM 0 0 0 0 0 0 119  1 μM 0 0 0 0 0 0 0.1 μM 0 00 0 0 0 0.01 μM 0 0 0 0 0 0 120  1 μM 0 0 0 0 0 0 0.1 μM 0 0 0 0 0 00.01 μM 0 0 0 0 0 0 A 30 μM 0 0 0 0 0 0 10 μM 0 0 0 0 0 0 3 μM 0 0 0 0 00 B 30 μM 0 0 0 0 0 0 10 μM 0 0 0 0 0 0 3 μM 0 0 0 0 0 00: no effect1: weak effect2: strong effectB) MTS Proliferation Assay

The assay is performed in 96 well tissue culture plates. The cells(range: 1.5*10³-10⁴) are seeded out in 80 μl complete medium 24 h priorto compound treatment. The test compounds are added in 20 μl completemedium containing max 5% DMSO. The final compound concentrations in theassays are 10 μM, 3 μM, 1 μM and 0.3 μM, respectively. The assay platesare incubated for 72 h at culture conditions. The MTS reagent isprepared according to the manufacturer's protocol (Promega G1111). 20 μlMTS reagent are added to each well, the assay plates are quickly spunand incubated for another 3 h at culture conditions. Subsequently, theplates are shortly shaked and absorption measured with amicroplate-reader at 492 nm. IC₅₀ values are determined by graphicalanalysis and are indicated in the Table 7 in μM concentration. TABLE 7MTS proliferation assay IC 50 No Jurkat Jily HT1080 HeLa MRC5  1 2 n.d.n.d. 1 0  2 0 n.d. n.d. 0 0  3 1 n.d. n.d. n.d. 0  4 2 1 1 1 1  5 1 n.d.n.d. 1 1  6 3 2 2 2 1  7 1 1 1 1 1  8 1 1 1 1 1  9 1 1 1 1 1 10 n.d. 2n.d. 1 n.d. 11 n.d. 2 n.d. 1 n.d. 12 1 1 0 0 0 13 1 1 1 1 1 14 2 2 2 2 215 3 3 3 2 3 16 1 2 2 1 2 17 0 n.d. n.d. 0 n.d. 18 1 n.d. n.d. 0 1 19 2n.d. n.d. 1 1 20 1 n.d. n.d. 0 0 21 0 n.d. n.d. 0 0 22 1 n.d. n.d. 1 123 1 n.d. n.d. 1 1 24 0 n.d. n.d. 0 0 25 1 n.d. n.d. 0 0 26 0 n.d. n.d.0 0 27 0 n.d. n.d. 0 0 28 0 n.d. n.d. 0 0 29 2 n.d. n.d. 2 2 30 1 n.d.n.d. 1 1 31 1 1 0 1 1 32 1 n.d. n.d. 1 0 33 0 n.d. n.d. 0 0 34 0 n.d.n.d. 0 0 35 2 2 1 2 1 36 2 2 1 2 1 37 1 n.d. n.d. 1 1 38 1 n.d. n.d. 1 039 0 n.d. n.d. 0 0 40 1 n.d. n.d. 1 0 41 1 1 1 1 1 42 2 2 2 2 1 43 1 1 11 1 44 3 2 2 2 2 45 2 2 2 2 1 46 3 2 2 2 1 47 3 3 2 2 1 48 3 2 2 2 2 491 1 0 0 0 50 2 2 2 2 2 51 2 2 2 2 2 52 n.d. 2 n.d. 2 n.d. 53 n.d. 2 n.d.2 n.d. 54 n.d. 2 2 2 2 55 n.d. 2 1 1 1 56 n.d. 2 2 2 2 57 2 2 1 1 1 58 33 3 2 3 59 1 1 1 1 1 60 1 1 1 1 1 61 2 2 2 2 2 62 2 2 2 1 2 63 0 n.d. 00 0 64 2 2 2 2 2 65 3 3 3 2 3 66 2 1 1 1 1 67 1 2 1 1 1 68 2 2 1 1 1 692 1 1 1 1 70 3 3 3 3 3 71 n.d. 1 0 1 0 72 1 1 1 1 1 73 1 1 1 1 1 74 1 11 1 1 75 1 1 1 1 1 76 1 2 1 1 1 77 1 1 1 1 1 78 3 3 3 3 3 79 3 3 3 3 380 81 82 83 84 85 86 87 88 1 1 1 1 1 89 2 2 2 2 1 90 1 1 1 1 1 91 1 1 11 1 92 2 2 2 2 1 93 2 2 1 1 1 94 2 2 2 2 1 95 1 1 1 1 1 96 1 1 1 1 1 971 1 1 1 1 98 1 1 0 0 0 99 1 1 0 0 0 100  1 0 0 0 0 101  n.d. 2 2 2 2102  n.d. 1 0 0 1 103  n.d. 2 1 1 1 104  105  106  107  108  1 1 1 1 1109  1 n.d. n.d. 0 0 110  0 n.d. 0 0 0 111  0 n.d. 0 0 0 112  0 n.d. 0 00 113  0 n.d. 0 0 0 114  0 n.d. 0 0 0 115  0 n.d. 0 0 0 116  0 n.d. 0 00 117  0 n.d. 0 0 0 118  0 0 0 0 0 119  0 0 0 0 0 120  0 0 0 0 0 A 0 0 00 0 B 0 0 0 0 00 IC 50 > 1 μM1 0.1 μM < IC 50 < 1 μM2 0.01 < IC 50 < 0.1 μM3 IC 50 < 0.01 μMC) Annexin V/7-AAD Staining

Adherent cells (1-2*10⁵) are 24 h prior to compound treatment seededinto 24 well tissue culture plates. Suspension cells are pipetted intoP-tubes immediately before treatment. Test compounds are added leadingto a final concentrations of 10 μM. After 24 h Treatment cells areharvested (in case of adherent cells by trypsinization) and transferredto FACS tubes (BD Biosciences). After centrifugation and removal of thesupernatant, 100 μl complete medium containing AnnexinV-GST (10 μg) isadded, mixed and incubated at 4° C. for 30 minutes. Subsequently, thecells are washed once with medium and incubated with 100 μl anti-GSTAlexa 488 (Molecular Probes A-11131) in medium diluted 1:500 for 30minutes at 4° C. Then, cells are washed once and stained with 1 μg/ml7-aminoactino-mycin D (7-AAD) (Molecular Probes A-1310) in 250 μL mediumand analyzed on the FACSCalibur™. AnnexinV is measured in FL1 whereas7-AAD is measured in FL3.

D) PI Staining for Cell Cycle Distribution

1-2*10⁵ cells are seeded into 24 well tissue culture plates andincubated for 24 h prior to compound addition. Compounds are added for24 h in a final concentration of 3 μM or 10 μM. Adherent cells areharvested by trypsinization. The cell suspensions are fixed by adding 2parts ice cold ethanol 100% while vortexing. Then the samples are storedfor >2 h at −20° C. Subsequently the cells are washed with PBS once andresuspended in 250 μl PBS containing 50 μg/ml PI (Calbiochem # 537059),then the samples are incubated at 37° C. for 30 minutes and subsequentlyanalyzed on a FACSCalibur™ monitoring linear PI fluorescence activity onFL2. The readout allows the detection of a possible direct or indirectinfluence of the tested compounds on the cell cycle. The followingevents can occur: a) Generation of a subG1 peak indicative for DNAfragmentation, b) increase of the cell population arrested in G2M phase.Both events are scored by 1 for weak and 2 for strong occurrence. 0indicates no occurrence at all. In Table 8 the influences of severaltested compounds are demonstrated. TABLE 8 Pl staining for cell cycledistribution Jurkat 3 μM HeLa 10 μM No subG1 G2M subG1 G2M 16 0 0 0 2 190 0 0 2 29 0 0 0 2 30 0 0 0 2 58 0 0 0 20: no effect1: weak effect2: strong effectE) BrdU Incorporation (Proliferation)

Adherent cells are seeded out at 2-4*10⁴ cells/well/ml in 24 well tissueculture plates 24 h prior to treatment. Suspension cells are seeded outat 2*10⁵ cells/ml/well in 24 well plates. Compounds are added leading tofinal concentrations of 3 μM and 10 μM, respectively. Subsequently, BrdU(Molecular Probes #B-23151) at 10 μM final concentration is added andthe plates are incubated for 48 h. After the incubation cells areprocessed according to standard procedures. The detection of theincorporated BrdU is done with the anti-bromodeoxyuridine Mab PRB-1,Alexa Fluor 660 conjugate (Molecular Probes #A-21306). The analysis isperformed on a FACSCalibur™ by monitoring the fluorescence activity onFL3. The readout reflects DNA synthesis which is a hallmark forproliferation.

F) Caspase Dependencies

Caspase dependencies are being evaluated by combining the compoundtreatment with the pan-caspase inhibitor ZVAD or its control peptide zFA(ICN Pharmaceuticals # FK009 and FK029, respectively). Both peptides arebeing used at 20 μM concentration. In case of caspase dependencies aclear inhibition of the specific readout in all apoptosis tests shouldbe detected. By comparing the readout of zVAD and zFA treated sampleswith the compound control it is possible to detect caspase resp. cysteinproteinase dependencies. In case of inhibition by ZVAD but not by zFA aclear caspase dependency is obvious. An inhibition by zVAD as well as byzFA points towards the involvement of cystein proteinases In theapoptotic cascade. Table 9 demonstrates the protease dependency of thenuclear fragmentation visualized by Hoechst 33342 staining.

Example 127 Soft Capsules

5000 soft gelatin capsules, each comprising as active ingredient 0.05 gof one of the compounds of formula (I) mentioned in the precedingExamples, are prepared as follows: 250 g pulverized active ingredient issuspended in 2 liter Lauroglykol® (propylene glycol laurate, GattefosséS. A., Saint Priest, France) and ground in a wet pulverizer to produce aparticle size of about 1 to 3 μm. 0.419 g portions of the mixture arethen introduced into soft gelatin capsules using a capsule-fillingmachine.

1. A compound of formula (I)

wherein R represents aryl or heteroaryl optionally substituted by up tofour substituents independently selected from alkyl, cycloalkyl,cycloalkyl-lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, loweralkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl, halo-loweralkoxy-lower alkyl, acyloxy-lower alkyl, heterocyclyl,heterocyclyl-lower alkyl, optionally substituted phenyl, optionallysubstituted phenyl-lower alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl-lower alkyl, optionally substitutedalkenyl, optionally substituted alkinyl, hydroxy, lower alkoxy,optionally substituted alkenyloxy, optionally substituted alkinyloxy,cycloalkoxy, halo-lower alkoxy, cycloalkyl-lower alkoxy, hydroxy-loweralkoxy, lower alkoxy-lower alkoxy, heterocyclyloxy, heterocyclyl-loweralkoxy, optionally substituted phenyloxy, optionally substitutedphenyl-lower alkoxy, optionally substituted heteroaryloxy, optionallysubstituted heteroaryl-lower alkoxy, sulfamoyloxy, carbamoyloxy, loweralkylcarbonyloxy, amino, monoalkylamino, dialkylamino,aminocarbonylamino wherein each of the two amino groups is optionallysubstituted by alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,heterocyclylcarbonylamino wherein heterocyclyl is bound via a nitrogenatom, aminosulfonylamino wherein each of the two amino groups isoptionally substituted by alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,heterocyclylsulfonylamino wherein heterocyclyl is bound via a nitrogenatom, lower alkoxycarbonylamino, lower alkylcarbonylamino wherein alkylis optionally substituted by one or two substituents selected fromoptionally substituted phenyl, guanidyl, halogen, cyano, alkoxy,optionally substituted phenoxy, alkylmercapto and optionally substitutedamino; lower alkenylcarbonylamino wherein alkenyl is optionallysubstituted by one or two substituents selected from lower alkyl,halo-lower alkyl, optionally substituted phenyl, halogen, cyano, alkoxyand optionally substituted amino; amino-lower alkyl or amino-loweralkylamino, wherein the nitrogen atom is unsubstituted or substituted byone or two substitutents selected from lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,optionally substituted phenyl, optionally substituted phenyl-loweralkyl, optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the twosubstituents on nitrogen form together with the nitrogen heterocyclyl,lower alkylcarbonyl, formyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl, hydroxy-loweralkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, optionallysubstituted phenyl-lower alkoxycarbonyl, cyano, lower alkylmercapto,optionally substituted phenylmercapto, lower alkylsulfinyl, halo-loweralkylsulfinyl, optionally substituted phenylsulfinyl, loweralkylsulfonyl, halo-lower alkylsulfonyl, optionally substitutedphenylsulfonyl, aralkylsulfonyl, halogen, and nitro; and wherein twoadjacent substituents together with the atoms of aryl or heteroaryl mayform a 5 or 6 membered carbocyclic or heterocyclic ring; X representsoxygen; a group C═Y, wherein Y stands for oxygen or nitrogen substitutedby hydroxy or alkoxy; or a group —CO—CH═CH— wherein the C═C bond isconnected to R; R¹ and R², independently of each other, representhydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, hydroxyalkyl,alkoxyalkyl, hydroxyalkoxyalkyl, alkoxyalkoxyalkyl, cyanoalkyl,optionally substituted alkenyl, optionally substituted alkinyl, or loweralkylcarbonyl wherein lower alkyl is optionally substituted by one ortwo substitutents selected from aryl, optionally substituted amino,alkoxy and aryloxy, R³, R⁴, R⁵ and R⁶, independently of each other,represent hydrogen, lower alkyl, halo-lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,lower alkoxy-lower alkoxy-lower alkyl, halo-lower alkoxy-lower alkyl,heterocyclyl, heterocyclyl-lower alkyl, optionally substituted phenyl,optionally substituted phenyl-lower alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl-lower alkyl, optionallysubstituted alkenyl, optionally substituted alkinyl, hydroxy, loweralkoxy, halo-lower alkoxy, cycloalkoxy, cycloalkyl-lower alkoxy,hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, heterocyclyloxy,heterocyclyl-lower alkoxy, optionally substituted phenyloxy, optionallysubstituted phenyl-lower alkoxy, optionally substituted heteroaryloxy,optionally substituted heteroaryl-lower alkoxy, amino, carbamoyl,sulfamoyl, amino-lower alkyl or amino-lower alkylamino, wherein in eachcase the nitrogen atom is unsubstituted or substituted by one or twosubstitutents selected from lower alkyl, cycloalkyl, cycloalkyl-loweralkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionallysubstituted phenyl, optionally substituted phenyl-lower alkyl,optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the twosubstituents on nitrogen form together with the nitrogen heterocyclyl,lower alkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl, hydroxy-loweralkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, optionallysubstituted phenyl-lower alkoxycarbonyl, cyano, lower alkylmercapto,optionally substituted phenylmercapto, lower alkylsulfinyl, halo-loweralkylsulfinyl, optionally substituted phenylsulfinyl, loweralkylsulfonyl, halo-lower alkylsulfonyl, optionally substitutedphenylsulfonyl, aralkylsulfonyl, halogen, or nitro, or R³ and R⁴, R⁴ andR⁵, or R⁵ and R⁶ together with the atoms of the phenyl ring form a 5 or6 membered carbocyclic or heterocyclic ring; and salts thereof.
 2. Acompound of formula (I) according to claim 1 wherein R represents arylor heteroaryl optionally substituted by up to four substituentsindependently selected from alkyl, cycloalkyl, cycloalkyl-lower alkyl,halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, loweralkoxy-lower alkoxy-lower alkyl, halo-lower alkoxy-lower alkyl,acyloxy-lower alkyl, heterocyclyl, heterocyclyl-lower alkyl, optionallysubstituted phenyl, optionally substituted phenyl-lower alkyl,optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl, optionally substituted alkenyl, optionallysubstituted alkinyl, hydroxy, lower alkoxy, optionally substitutedalkenyloxy, optionally substituted alkinyloxy, cycloalkoxy, halo-loweralkoxy, cycloalkyl-lower alkoxy, hydroxy-lower alkoxy, loweralkoxy-lower alkoxy, heterocyclyloxy, heterocyclyl-lower alkoxy,optionally substituted phenyloxy, optionally substituted phenyl-loweralkoxy, optionally substituted heteroaryloxy, optionally substitutedheteroaryl-lower alkoxy, sulfamoyloxy, carbamoyloxy, loweralkylcarbonyloxy, amino, monoalkylamino, dialkylamino,aminocarbonylamino wherein each of the two amino groups is optionallysubstituted by alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,heterocyclylcarbonylamino wherein heterocyclyl is bound via a nitrogenatom, aminosulfonylamino wherein each of the two amino groups isoptionally substituted by alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,heterocyclylsulfonylamino wherein heterocyclyl is bound via a nitrogenatom, lower alkoxycarbonylamino, lower alkylcarbonylamino wherein alkylis optionally substituted by one or two substituents selected fromoptionally substituted phenyl, guanidyl, halogen, cyano, alkoxy,optionally substituted phenoxy, alkylmercapto and optionally substitutedamino; lower alkenylcarbonylamino wherein alkenyl is optionallysubstituted by one or two substituents selected from lower alkyl,halo-lower alkyl, optionally substituted phenyl, halogen, cyano, alkoxyand optionally substituted amino; amino-lower alkyl or amino-loweralkylamino, wherein the nitrogen atom is unsubstituted or substituted byone or two substitutents selected from lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,optionally substituted phenyl, optionally substituted phenyl-loweralkyl, optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the twosubstituents on nitrogen form together with the nitrogen heterocyclyl,lower alkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl, hydroxy-loweralkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, optionallysubstituted phenyl-lower alkoxycarbonyl, cyano, lower alkylmercapto,optionally substituted phenylmercapto, lower alkylsulfinyl, halo-loweralkylsulfinyl, optionally substituted phenylsulfinyl, loweralkylsulfonyl, halo-lower alkylsulfonyl, optionally substitutedphenylsulfonyl, aralkylsulfonyl, halogen, and nitro; and wherein twoadjacent substituents together with the atoms of aryl or heteroaryl mayform a 5 or 6 membered carbocyclic or heterocyclic ring; X representsoxygen; or a group C═Y, wherein Y stands for oxygen, nitrogensubstituted by hydroxy or alkoxy; R¹ and R², independently of eachother, represent hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl,alkoxyalkoxyalkyl, cyanoalkyl, optionally substituted alkenyl,optionally substituted alkinyl, or lower alkylcarbonyl wherein loweralkyl is optionally substituted by one or two substitutents selectedfrom aryl, optionally substituted amino, alkoxy and aryloxy, R³, R⁴, R⁵and R⁶, independently of each other, represent hydrogen, lower alkyl,halo-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl,halo-lower alkoxy-lower alkyl, heterocyclyl, heterocyclyl-lower alkyl,optionally substituted phenyl, optionally substituted phenyl-loweralkyl, optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl, optionally substituted alkenyl, optionallysubstituted alkinyl, hydroxy, lower alkoxy, halo-lower alkoxy,cycloalkoxy, cycloalkyl-lower alkoxy, hydroxy-lower alkoxy, loweralkoxy-lower alkoxy, heterocyclyloxy, heterocyclyl-lower alkoxy,optionally substituted phenyloxy, optionally substituted phenyl-loweralkoxy, optionally substituted heteroaryloxy, optionally substitutedheteroaryl-lower alkoxy, amino, carbamoyl, sulfamoyl, amino-lower alkylor amino-lower alkylamino, wherein in each case the nitrogen atom isunsubstituted or substituted by one or two substitutents selected fromlower alkyl, cycloalkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl,lower alkoxy-lower alkyl, optionally substituted phenyl, optionallysubstituted phenyl-lower alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl-lower alkyl and lower alkylcarbonyl,or wherein the two substituents on nitrogen form together with thenitrogen heterocyclyl, lower alkylcarbonyl, cycloalkylcarbonyl,optionally substituted phenylcarbonyl, optionally substitutedheteroarylcarbonyl, heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl,hydroxy-lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl,optionally substituted phenyl-lower alkoxycarbonyl, cyano, loweralkylmercapto, optionally substituted phenylmercapto, loweralkylsulfinyl, halo-lower alkylsulfinyl, optionally substitutedphenylsulfinyl, lower alkylsulfonyl, halo-lower alkylsulfonyl,optionally substituted phenylsulfonyl, aralkylsulfonyl, halogen, ornitro, or R³ and R⁴, R⁴ and R⁵, or R⁵ and Re together with the atoms ofthe phenyl ring form a 5 or 6 membered carbocyclic or heterocyclic ring;and salts thereof.
 3. A compound of formula (I) according to claim 2,wherein R represents phenyl, naphthyl, thienyl, furyl, thiazolyl,oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, pyridinyl,pyrimidinyl, benzothienyl, benzofuryl, indolyl, benzoisoxazolyl,optionally substituted by up to four substituents independently selectedfrom alkyl, cycloalkyl, cycloalkyl-lower alkyl, halo-lower alkyl,hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxy-loweralkoxy-lower alkyl, halo-lower alkoxy-lower alkyl, acyloxy-lower alkyl,heterocyclyl, heterocyclyl-lower alkyl, optionally substituted phenyl,optionally substituted phenyl-lower alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl-lower alkyl, optionallysubstituted alkenyl, optionally substituted alkinyl, hydroxy, loweralkoxy, optionally substituted alkenyloxy, optionally substitutedalkinyloxy, cycloalkoxy, halo-lower alkoxy, cycloalkyl-lower alkoxy,hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, heterocyclyloxy,heterocyclyl-lower alkoxy, optionally substituted phenyloxy, optionallysubstituted phenyl-lower alkoxy, optionally substituted heteroaryloxy,optionally substituted heteroaryl-lower alkoxy, sulfamoyloxy,carbamoyloxy, lower alkylcarbonyloxy, amino, monoalkylamino,dialkylamino, aminocarbonylamino wherein each of the two amino groups isoptionally substituted by alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,heterocyclylcarbonylamino wherein heterocyclyl is bound via a nitrogenatom, aminosulfonylamino wherein each of the two amino groups isoptionally substituted by alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,heterocyclylsulfonylamino wherein heterocyclyl is bound via a nitrogenatom, lower alkoxycarbonylamino, lower alkylcarbonylamino wherein alkylis optionally substituted by one or two substituents selected fromoptionally substituted phenyl, guanidyl, halogen, cyano, alkoxy,optionally substituted phenoxy, alkylmercapto and optionally substitutedamino; lower alkenylcarbonylamino wherein alkenyl is optionallysubstituted by one or two substituents selected from lower alkyl,halo-lower alkyl, optionally substituted phenyl, halogen, cyano, alkoxyand optionally substituted amino; amino-lower alkyl or amino-loweralkylamino, wherein the nitrogen atom is unsubstituted or substituted byone or two substitutents selected from lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,optionally substituted phenyl, optionally substituted phenyl-loweralkyl, optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the twosubstituents on nitrogen form together with the nitrogen heterocyclyl,lower alkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl, hydroxy-loweralkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, optionallysubstituted phenyl-lower alkoxycarbonyl, cyano, lower alkylmercapto,optionally substituted phenylmercapto, lower alkylsulfinyl, halo-loweralkylsulfinyl, optionally substituted phenylsulfinyl, loweralkylsulfonyl, halo-lower alkylsulfonyl, optionally substitutedphenylsulfonyl, aralkylsulfonyl, halogen, and nitro; and wherein twoadjacent substituents together with the atoms of aryl or heteroaryl mayform a 5 or 6 membered carbocyclic or heterocyclic ring; X representsoxygen; or a group C═Y, wherein Y stands for oxygen or nitrogensubstituted by hydroxy or alkoxy; R¹ and R², independently of eachother, represent hydrogen, lower alkylcarbonyl or optionally substitutedphenylcarbonyl; R³, R⁴, R⁵ and R⁵, independently of each other,represent hydrogen, lower alkyl, halo-lower alkyl, alkoxy, hydroxy-loweralkoxy, lower alkoxy-lower alkoxy, amino, carbamoyl, sulfamoyl,amino-lower alkyl or amino-lower alkylamino, wherein in each case thenitrogen atom is unsubstituted or substituted by one or twosubstitutents selected from lower alkyl, cycloalkyl, cycloalkyl-loweralkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionallysubstituted phenyl, optionally substituted phenyl-lower alkyl,optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl and lower alkylaminocarbonyl, or wherein the twosubstituents on nitrogen form together with the nitrogen heterocyclyl,carboxy, lower alkoxycarbonyl, hydroxy-lower alkoxycarbonyl, loweralkoxy-lower alkoxycarbonyl, optionally substituted phenyl-loweralkoxycarbonyl, cyano, lower alkylmercapto, optionally substitutedphenylmercapto, lower alkylsulfinyl, halo-lower alkylsulfinyl,optionally substituted phenylsulfinyl, lower alkylsulfonyl, halo-loweralkylsulfonyl, optionally substituted phenylsulfonyl, aralkylsulfonyl,halogen, or nitro, or R³ and R⁴, R⁴ and R⁵, or R⁵ and R⁶ togetherrepresent methylenedioxy; and salts thereof.
 4. A compound of formula(I) according to claim 2, wherein R represents phenyl, naphthyl,thienyl, furyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl,pyrazolyl, pyridinyl, pydimidinyl, benzothienyl, benzofuryl, indolyl,benzoisoxazolyl, optionally substituted by up to four substituentsindependently selected from alkyl, halo-lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl,halo-lower alkoxy-lower alkyl, acyloxy-lower alkyl, heterocyclyl,heterocyclyl-lower alkyl, optionally substituted phenyl, optionallysubstituted phenyl-lower alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl-lower alkyl, optionally substitutedalkenyl, optionally substituted alkinyl, hydroxy, lower alkoxy,optionally substituted alkenyloxy, optionally substituted alkinyloxy,cycloalkoxy, halo-lower alkoxy, cycloalkyl-lower alkoxy, hydroxy-loweralkoxy, lower alkoxy-lower alkoxy, heterocyclyloxy, heterocyclyl-loweralkoxy, optionally substituted phenyloxy, optionally substitutedphenyl-lower alkoxy, optionally substituted heteroaryloxy, optionallysubstituted heteroaryl-lower alkoxy, sulfamoyloxy, carbamoyloxy, loweralkylcarbonyloxy, amino, monoalkylamino, dialkylamino,aminocarbonylamino wherein each of the two amino groups is optionallysubstituted by alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,heterocyclylcarbonylamino wherein heterocyclyl is bound via a nitrogenatom, aminosulfonylamino wherein each of the two amino groups isoptionally substituted by alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,heterocyclylsulfonylamino wherein heterocyclyl is bound via a nitrogenatom, lower alkoxycarbonylamino, lower alkylcarbonylamino wherein alkylis optionally substituted by one or two substituents selected fromoptionally substituted phenyl, guanidyl, halogen, cyano, alkoxy,optionally substituted phenoxy, alkylmercapto and optionally substitutedamino; lower alkenylcarbonylamino wherein alkenyl is optionallysubstituted by one or two substituents selected from lower alkyl,halo-lower alkyl, optionally substituted phenyl, halogen, cyano, alkoxyand optionally substituted amino; amino-lower alkyl or amino-loweralkylamino, wherein the nitrogen atom is unsubstituted or substituted byone or two substitutents selected from lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,optionally substituted phenyl, optionally substituted phenyl-loweralkyl, optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the twosubstituents on nitrogen form together with the nitrogen heterocyclyl,lower alkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl, hydroxy-loweralkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, optionallysubstituted phenyl-lower alkoxycarbonyl, cyano, lower alkylmercapto,optionally substituted phenylmercapto, lower alkylsulfinyl, halo-loweralkylsulfinyl, optionally substituted phenylsulfinyl, loweralkylsulfonyl, halo-lower alkylsulfonyl, optionally substitutedphenylsulfonyl, aralkylsulfonyl, halogen, and nitro; and wherein twoadjacent substituents together with the atoms of aryl or heteroaryl mayform a 5 or 6 membered carbocyclic or heterocyclic ring; X represents agroup C═Y, wherein Y stands for oxygen or nitrogen substituted byhydroxy or alkoxy; R¹ and R², independently of each other, representhydrogen or lower alkylcarbonyl; R³, R⁴, R⁵ and R⁶, independently ofeach other, represent hydrogen, lower alkyl, halo-lower alkyl, hydroxy,lower alkoxy, carboxy, lower alkoxycarbonyl, cyano, halogen or nitro;and salts thereof.
 5. A compound according to claim 2 selected from thegroup consisting of4-(1-Phenacyl-1H-benzimidazol-2-yl)-furazan-3-ylamine;4-(1-Phenacyl-1H-benzimidazol-2-yl)-furazan-3-ylamine oxime;4-(1-Phenacyl-1H-benzimidazol-2-yl)-furazan-3-ylamine oxime methylether; 4-[1-(4-Bromophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;4-[1-(4-Bromophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine oxime;4-[1-(4-Bromophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine oximemethyl ether;4-[1-(4-Chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;4-[1-(4-Chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine oxime;4-[1-(4-Chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine oximemethyl ether;4-[1-(4-Methoxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;4-[1-(4-Methoxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine oxime;4-[1-(3-Methoxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;4-[1-(3-Methoxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine oxime;4-[1-(3-Methoxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine oximemethyl ether;4-[1-(4-Phenylphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;4-[1-(4-Phenylphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine oxime;4-[1-(4-Phenylphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine oximemethyl ether; and4-[1-(2,4-Dichlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine; andpharmaceutically acceptable salts thereof.
 6. A compound of formula (I)according to claim 1, wherein R represents phenyl, naphthyl, thienyl,furyl, thiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,pyridinyl, pyrimidinyl, benzothienyl, benzofuryl, indolyl,benzoisoxazolyl, optionally substituted by up to four substituentsindependently selected from alkyl, halo-lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl,halo-lower alkoxy-lower alkyl, acyloxy-lower alkyl, heterocyclyl,heterocyclyl-lower alkyl, optionally substituted phenyl, optionallysubstituted phenyl-lower alkyl, optionally substituted heteroaryl,optionally substituted heteroaryl-lower alkyl, optionally substitutedalkenyl, optionally substituted alkinyl, hydroxy, lower alkoxy,optionally substituted alkenyloxy, optionally substituted alkinyloxy,cycloalkoxy, halo-lower alkoxy, cycloalkyl-lower alkoxy, hydroxy-loweralkoxy, lower alkoxy-lower alkoxy, heterocyclyloxy, heterocyclyl-loweralkoxy, optionally substituted phenyloxy, optionally substitutedphenyl-lower alkoxy, optionally substituted heteroaryloxy, optionallysubstituted heteroaryl-lower alkoxy, sulfamoyloxy, carbamoyloxy, loweralkylcarbonyloxy, amino, monoalkylamino, dialkylamino,aminocarbonylamino wherein each of the two amino groups is optionallysubstituted by alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,heterocyclylcarbonylamino wherein heterocyclyl is bound via a nitrogenatom, aminosulfonylamino wherein each of the two amino groups isoptionally substituted by alkyl, alkenyl, alkinyl or alkoxy-lower alkyl,heterocyclylsulfonylamino wherein heterocyclyl is bound via a nitrogenatom, lower alkoxycarbonylamino, lower alkylcarbonylamino wherein alkylis optionally substituted by one or two substituents selected fromoptionally substituted phenyl, guanidyl, halogen, cyano, alkoxy,optionally substituted phenoxy, alkylmercapto and optionally substitutedamino; lower alkenylcarbonylamino wherein alkenyl is optionallysubstituted by one or two substituents selected from lower alkyl,halo-lower alkyl, optionally substituted phenyl, halogen, cyano, alkoxyand optionally substituted amino; amino-lower alkyl or amino-loweralkylamino, wherein the nitrogen atom is unsubstituted or substituted byone or two substitutents selected from lower alkyl, cycloalkyl,cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,optionally substituted phenyl, optionally substituted phenyl-loweralkyl, optionally substituted heteroaryl, optionally substitutedheteroaryl-lower alkyl and lower alkylcarbonyl, or wherein the twosubstituents on nitrogen form together with the nitrogen heterocyclyl,lower alkylcarbonyl, cycloalkylcarbonyl, optionally substitutedphenylcarbonyl, optionally substituted heteroarylcarbonyl,heterocyclylcarbonyl, carboxy, lower alkoxycarbonyl, hydroxy-loweralkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl, optionallysubstituted phenyl-lower alkoxycarbonyl, cyano, lower alkylmercapto,optionally substituted phenylmercapto, lower alkylsulfinyl, halo-loweralkylsulfinyl, optionally substituted phenylsulfinyl, loweralkylsulfonyl, halo-lower alkylsulfonyl, optionally substitutedphenylsulfonyl, aralkylsulfonyl, halogen, and nitro; and wherein twoadjacent substituents together with the atoms of aryl or heteroaryl mayform a 5 or 6 membered carbocyclic or heterocyclic ring; X represents agroup C═Y, wherein Y stands for oxygen or nitrogen substituted byhydroxy or alkoxy; R¹ represents cyanoalkyl; R² represents hydrogen; R³,R⁴, R⁵ and R⁶, independently of each other, represent hydrogen, loweralkyl, halo-lower alkyl, hydroxy, lower alkoxy, carboxy, loweralkoxycarbonyl, cyano, halogen or nitro; and salts thereof.
 7. Acompound of formula (I) according to claim 1 wherein R, X and R² to R⁶are as defined for claim 6 and R¹ represents hydroxyalkyl, and saltsthereof.
 8. A compound of formula (I) according to claim 1 wherein Rrepresents phenyl, thienyl, pyridinyl or pyridazinyl, optionallysubstituted by one or two substituents independently selected fromalkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-loweralkoxy, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, loweralkylcarbonyloxy, amino, monoalkylamino, dialkylamino, loweralkoxycarbonylamino, lower alkylcarbonylamino, substituted amino whereinthe two substituents on nitrogen form together with the nitrogenheterocyclyl, lower alkylcarbonyl, formyl, carboxy, loweralkoxycarbonyl, cyano, halogen, and nitro; and wherein two adjacentsubstituents are methylenedioxy; X represents oxygen; a group C═Y,wherein Y stands for oxygen or nitrogen substituted by hydroxy oralkoxy; or a group —CO—CH═CH— wherein the C═C bond is connected to R; Rrepresents hydrogen, lower alkylcarbonyl, hydroxy-lower alkyl orcyano-lower alkyl; R², R³ and Re represent hydrogen; R⁴ and R⁵,independently of each other, represent hydrogen, lower alkyl or loweralkoxy; or R⁴ and R⁵ together represent methylenedioxy; and saltsthereof.
 9. A compound of formula (I) according to claim 8 wherein Rrepresents phenyl, thienyl, pyridinyl or pyridazinyl, wherein phenyl isoptionally substituted by one or two substituents independently selectedfrom alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-loweralkyl, acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-loweralkoxy, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, loweralkylcarbonyloxy, amino, monoalkylamino, dialkylamino, loweralkoxycarbonylamino, lower alkylcarbonylamino, substituted amino whereinthe two substituents on nitrogen form together with the nitrogenheterocyclyl, lower alkylcarbonyl, formyl, carboxy, loweralkoxycarbonyl, cyano, halogen, and nitro; and wherein two adjacentsubstituents are methylenedioxy; and wherein pyridinyl or pyridazinylare optionally substituted by lower alkoxy, amino or halogen; Xrepresents a group C═Y, wherein Y stands for oxygen or nitrogensubstituted by hydroxy or lower alkoxy; R¹ represents hydrogen, loweralkylcarbonyl, hydroxy-lower alkyl or cyano-lower alkyl; R², R³ and R⁶represent hydrogen; R⁴ and R⁵, independently of each other, representhydrogen, lower alkyl or lower alkoxy; or R⁴ and R⁵ together representmethylenedioxy; and pharmaceutically acceptable salts thereof.
 10. Acompound of formula (I) according to claim 8 wherein R representsphenyl, thienyl or pyridinyl wherein phenyl is optionally substituted byone or two substituents independently selected from alkyl, halo-loweralkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, acyloxy-loweralkyl, phenyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, loweralkoxy-lower alkoxy, phenyl-lower alkoxy, lower alkylcarbonyloxy, amino,monoalkylamino, dialkylamino, lower alkoxycarbonylamino, loweralkylcarbonylamino, substituted amino wherein the two substituents onnitrogen form together with the nitrogen heterocyclyl, loweralkylcarbonyl, carboxy, lower alkoxycarbonyl, cyano, halogen, and nitro;and wherein two adjacent substituents are methylenedioxy; and whereinpyridinyl is optionally substituted by lower alkoxy, amino or halogen; Xrepresents a group C═Y, wherein Y stands for oxygen or nitrogensubstituted by hydroxy or lower alkoxy; R¹ represents hydrogen, loweralkylcarbonyl, hydroxy-lower alkyl or cyano-lower alkyl; R², R³ and R⁶represent hydrogen; R⁴ and R⁵, independently of each other, representhydrogen, lower alkyl or lower alkoxy; or R⁴ and R⁵ together representmethylenedioxy; and pharmaceutically acceptable salts thereof.
 11. Acompound of formula (I) according to claim 8 wherein R representsphenyl, thienyl, pyridinyl or pyridazinyl, wherein phenyl is optionallysubstituted by one or two substituents independently selected fromalkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl,acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-loweralkoxy, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, loweralkylcarbonyloxy, amino, monoalkylamino, dialkylamino, loweralkoxycarbonylamino, lower alkylcarbonylamino, substituted amino whereinthe two substituents on nitrogen form together with the nitrogenheterocyclyl, lower alkylcarbonyl, formyl, carboxy, loweralkoxycarbonyl, cyano, halogen, and nitro; and wherein two adjacentsubstituents are methylenedioxy; and wherein pyridinyl or pyridazinylare optionally substituted by lower alkoxy, amino or halogen; Xrepresents a group C═Y, wherein Y stands for oxygen or nitrogensubstituted by hydroxy or lower alkoxy; R¹ represents cyano-lower alkyl;R², R³ and R⁶ represent hydrogen; R⁴ and R⁵, independently of eachother, represent hydrogen, lower alkyl or lower alkoxy; or R⁴ and R⁵together represent methylenedioxy; and pharmaceutically acceptable saltsthereof.
 12. A compound of formula (I) according to claim 8 wherein Rrepresents phenyl or pyridinyl wherein phenyl is optionally substitutedby one or two substituents independently selected from alkyl, halo-loweralkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, acyloxy-loweralkyl, phenyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, loweralkoxy-lower alkoxy, phenyl-lower alkoxy, lower alkylcarbonyloxy, amino,monoalkylamino, dialkylamino, lower alkoxycarbonylamino, loweralkylcarbonylamino, substituted amino wherein the two substituents onnitrogen form together with the nitrogen heterocyclyl, loweralkylcarbonyl, carboxy, lower alkoxycarbonyl, formyl, cyano, halogen,and nitro; and wherein two adjacent substituents are methylenedioxy; andwherein pyridinyl is optionally substituted by lower alkoxy, amino orhalogen; X represents oxygen; R¹ represents hydrogen, loweralkylcarbonyl, hydroxy-lower alkyl or cyano-lower alkyl; R², R³ and R⁶represent hydrogen; R⁴ and R⁵, independently of each other, representhydrogen, lower alkyl or lower alkoxy; or R⁴ and R⁵ together representmethylenedioxy; and pharmaceutically acceptable salts thereof.
 13. Acompound of formula (I) according to claim 8 wherein R and R¹ to R⁶ aredefined as in claim 12 and X represents nitrogen substituted by alkoxy;and pharmaceutically acceptable salts thereof.
 14. A compound of formula(I) according to claim 8 wherein R represents phenyl or pyridinylwherein phenyl is optionally substituted by one or two substituentsindependently selected from alkyl, halo-lower alkyl, hydroxy-loweralkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy,lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy,phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino,dialkylamino, lower alkoxycarbonylamino, lower alkylcarbonylamino,substituted amino wherein the two substituents on nitrogen form togetherwith the nitrogen heterocyclyl, lower alkylcarbonyl, carboxy, loweralkoxycarbonyl, formyl, cyano, halogen, and nitro; and wherein twoadjacent substituents are methylenedioxy; and wherein pyridinyl isoptionally substituted by lower alkoxy, amino or halogen; X representsoxygen; R¹ represents cyano-lower alkyl; R², R³, R⁴, R⁵ and R⁶ representhydrogen; and pharmaceutically acceptable salts thereof.
 15. A compoundof formula (I) according to claim 8 wherein R represents phenyl orpyridinyl wherein phenyl is optionally substituted by one or twosubstituents independently selected from alkyl, lower alkoxy-loweralkyl, acyloxy-lower alkyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy,lower alkoxy-lower alkoxy, amino, monoalkylamino, dialkylamino, loweralkoxycarbonylamino, lower alkylcarbonylamino, substituted amino whereinthe two substituents on nitrogen form together with the nitrogenheterocyclyl, halogen, and nitro; and wherein two adjacent substituentsare methylenedioxy; and wherein pyridinyl is optionally substituted bylower alkoxy, amino or halogen; X represents oxygen; R¹ representscyano-lower alkyl; R², R³, R⁴, R⁵ and R⁶ represent hydrogen; andpharmaceutically acceptable salts thereof.
 16. A compound of formula (I)according to claim 8 wherein R represents phenyl or pyridinyl whereinphenyl is optionally substituted by one or two substituentsindependently selected from alkyl, lower alkoxy-lower alkyl,acyloxy-lower alkyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, loweralkoxy-lower alkoxy, amino, monoalkylamino, dialkylamino, loweralkoxycarbonylamino, lower alkylcarbonylamino, substituted amino whereinthe two substituents on nitrogen form together with the nitrogenheterocyclyl, halogen, and nitro; and wherein two adjacent substituentsare methylenedioxy; and wherein pyridinyl is optionally substituted bylower alkoxy, amino or halogen; X represents nitrogen substituted byalkoxy; R¹ represents cyano-lower alkyl; R², R³, R⁴, R⁵ and R⁶ representhydrogen; and pharmaceutically acceptable salts thereof.
 17. A compoundof formula (I) according to claim 8 wherein R represents phenyloptionally substituted by one or two substituents independently selectedfrom alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-loweralkyl, acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-loweralkoxy, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, loweralkylcarbonyloxy, amino, monoalkylamino, dialkylamino, loweralkoxycarbonylamino, lower alkylcarbonylamino, substituted amino whereinthe two substituents on nitrogen form together with the nitrogenheterocyclyl, lower alkylcarbonyl, carboxy, lower alkoxycarbonyl, cyano,halogen, and nitro; and wherein two adjacent substituents aremethylenedioxy; X represents a group —CO—CH═CH— wherein the C═C bond isconnected to R; R¹ represents cyano-lower alkyl; R², R³, R⁴, R⁵ and R⁶represent hydrogen; and pharmaceutically acceptable salts thereof.
 18. Acompound according to claim 8 selected from the group consisting of4-[1-(4-Chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine;4-[1-(3-Methoxy-4-methoxymethoxy-phenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;4-[1-(4-Bromophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine;4-[1-(4-Aminophenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine;4-[1<4-Methoxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine;4-[1-(3,4-Dimethylphenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine;4-[1-(4-Ethylphenacyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine;4-[1-(6-Chloro-3-pyridyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;4-[1-(6-Amino-3-pyridyl)-1H-benzimidazol-2-yl]-furazan-3-yl-N-(2-cyanoethyl)-amine;and 4-[1-(6-Amino-3-pyridyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine;and pharmaceutically acceptable salts thereof.
 19. A method for thepreparation of a compound of formula (I) according to claim 1, whereinA) a compound of formula (II)

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are defined as for formula (I), or aderivative thereof with functional groups in protected form and/or asalt thereof, is alkylated with an alkylating agent of formula (III)R—X—CH₂-Z  (III) wherein R is as defined for formula (I), X is CO or—CO—CH═CH— and Z is a nucleophilic leaving group; or B) a compound offormula (II), wherein R¹, R², R³, R⁴, R⁵ and R⁶ are defined as forformula (I), or a derivative thereof with functional groups in protectedform and/or a salt thereof, is alkylated with a mixture of adihalomethane type compound of formula Z¹-CH₂-Z² (IV), wherein Z¹ and Z²are leaving groups, and a compound of formula R—XH (V), wherein R is asdefined for formula (I) and X is oxygen; any protecting groups in aprotected derivative of a compound of the formula (I) are removed; and,if so desired, an obtainable compound of formula (I) is converted intoanother compound of formula (I), a free compound of formula (I) isconverted into a salt, an obtainable salt of a compound of formula (I)is converted into the free compound or another salt, and/or a mixture ofisomeric compounds of formula (I) is separated into the individualisomers.
 20. A pharmaceutical composition comprising a compound offormula (I) according to claim 1 and a pharmaceutically acceptablecarrier.
 21. Use of a compound of formula (I) according to claim 1, aprodrug or a pharmaceutically acceptable salt of such a compound for thepreparation of a pharmaceutical composition for the treatment of aneoplastic disease, autoimmune disease, transplantation relatedpathology and/or degenerative disease.
 22. The use according to claim 21of a compound of formula (I) according to claim 1, or a pharmaceuticallyacceptable salt of such a compound for the preparation of apharmaceutical composition for the treatment of a solid neoplasticdisease.